Oxindole hydrazide modulators of protein tyrosine phosphatases (PTPs)

ABSTRACT

The present invention is related to the use of oxindole hydrazide derivatives of formula (I) for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type I and/or II, inadequate glucose tolerance, insulin resistance, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS). In particular, the present invention is related to the use of oxindole hydrazide derivatives of formula (I) to modulate, notably to inhibit the activity of PTPs, in particular of PTP1B, TC-PTP, SHP and GLEPP-1. The present invention is furthermore related to novel oxindole hydrazide derivatives and method of preparation thereof.(I).

FIELD OF THE INVENTION

The present invention is related to the use of oxindole hydrazidederivatives of formula (I) for the treatment and/or prevention ofmetabolic disorders mediated by insulin resistance or hyperglycemia,comprising diabetes type I and/or II, inadequate glucose tolerance,insulin resistance, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS). Thecompounds of this invention are particularly useful in the treatment oftype II or I diabetes. The compounds of this invention are thereforeuseful for the preparation of a pharmaceutical composition for thetreatment and/or prevention of metabolic disorders mediated by insulinresistance or hyperglycemia, comprising diabetes type I and/or II,inadequate glucose tolerance, insulin resistance, obesity, polycysticovary syndrome (PCOS).

Specifically, the present invention is related to the use of oxindolehydrazides as medicament and the use of oxindole hydrazide derivativesto modulate, notably to inhibit the activity of PTPs, in particular ofPTP1B, TC-PTP, SHP and GLEPP-1. The present invention is furthermorerelated to novel oxindole hydrazide derivatives and a method ofpreparing them.

BACKGROUND OF THE INVENTION

The prevalence of insulin resistance in glucose intolerant subjects iswell known. Reaven et al (American Journal of Medicine 1976, 60, 80)used a continuous infusion of glucose and insulin (insulin/glucose clamptechnique) and oral glucose tolerance tests to demonstrate that insulinresistance exists in a diverse group of non-obese, non-ketotic subjects.These subjects ranged from borderline glucose tolerant to overt, fastinghyperglycemia. The diabetic groups in these studies included bothinsulin dependent (IDDM) and non-insulin dependent (NIDDM) subjects.

Coincident with sustained insulin resistance is the more easilydetermined hyperinsulinemia, which may be measured by accuratedetermination of circulating plasma insulin concentration in the plasmaof subjects. Hyperinsulinemia may be present as a result of insulinresistance, such as is in obese and/or diabetic (NIDDM) subjects and/orglucose intolerant subjects, or in IDDM subjects, as a consequence ofover injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.

The association of hyperinsulinemia and insulin resistance with obesityand with ischemic diseases of the large blood vessels (e.g.atherosclerosis) has been well established by numerous experimental,clinical and epidemiological studies (Stout, Metabolism 1985, 34, 7).Statistically significant plasma insulin elevations at 1 and 2 hoursafter oral glucose load correlate with an increased risk of coronaryheart disease.

Since most of these studies actually excluded diabetic subjects, datarelating the risk of atherosclerotic diseases to the diabetic conditionare not as numerous, but point in the same direction as for non-diabeticsubjects. However, the incidence of atherosclerotic diseases inmorbidity and mortality statistics in the diabetic population exceedsthat of the nondiabetic population (Pyorala et al; JarrettDiabetes/Metabolism Reviews 1989, 5, 547).

The association of hyperinsulinemia and insulin resistance withPolycystic Ovary Syndrome (PCOS) is also well acknowledged(Diamanti-Kandarakis et al.; Therapeutic effects of metformin on insulinresistance and hyperandrogenism in polycystic ovary syndrome; EuropeanJournal of Endocrinology (1998) 138 269-274, Andrea Dunaif; InsulinResistance and the Polycystic Ovary Syndrome : Mechanism andImplications for Pathogenesis; Endocrine Reviews 18(6): 774-800).

The independent risk factors obesity and hypertension foratherosclerotic diseases are also associated with insulin resistance.Using a combination of insulin/glucose clamps, tracer glucose infusionand indirect calorimetry, it was demonstrated that the insulinresistance of essential hypertension is located in peripheral tissues(principally muscle) and correlates directly with the severity ofhypertension (DeFronzo and Ferrannini, Diabetes Care 1991, 14, 173). Inhypertension of obese people, insulin resistance generateshyperinsulinemia, which is recruited as a mechanism to limit furtherweight gain via thermogenesis, but insulin also increases renal sodiumre-absorption and stimulates the sympathetic nervous system in kidneys,heart, and vasculature, creating hypertension.

It is assumed that insulin resistance is usually the result of a defectin the insulin receptor signaling system, at a site post binding ofinsulin to the receptor. Accumulated scientific evidence demonstratinginsulin resistance in the major tissues which respond to insulin(muscle, liver, adipose), strongly suggests that a defect in insulinsignal transduction resides at an early step in this cascade,specifically at the insulin receptor kinase activity, which appears tobe diminished (Mounib Elchebly, Alan Cheng, Michel L. Tremblay;Modulation of insulin signaling by protein tyrosine phosphatases; J.Mol. Med. (2000) 78:473-482).

Protein-tyrosine phosphatases (PTPs) play an important role in theregulation of phosphorylation of proteins and represent the counterpartsof kinases. Among classical PTPs, there are two types : (i) non-receptoror intracellular PTPs; and (ii) receptor-like PTPs. Most intracellularPTPs contain one catalytic domain only, whereas most receptor-likeenzymes contain two. The catalytic domain consists of about 250 aminoacids (Niels Peter Hundahl Moller et al. Protein tyrosine phosphatases(PTPs) as drug targets: Inhibitors of PTP-1B for the treatment ofdiabetes; Current Opinion in Drug Discovery & Development 20003(5):527-540).

The interaction of insulin with its receptor leads to phosphorylation ofcertain tyrosine molecules within the receptor protein, thus activatingthe receptor kinase. PTPs dephosphorylate the activated insulinreceptor, attenuating the tyrosine kinase activity. PTPs can alsomodulate post-receptor signaling by catalyzing the dephosphorylation ofcellular substrates of the insulin receptor kinase. The enzymes thatappear most likely to closely associate with the insulin receptor andtherefore, most likely to regulate the insulin receptor kinase activity,include PTP1B, LAR, PTP-alpha. and SH-PTP2 (Lori Klaman et al.;Increased Energy Expenditure, Decreased Adiposity, and Tissue-specificinsulin sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice;Molecular and Cellular Biology 2000, 5479-5489).

PTP1B is a member of the PTP family. This 50 kDa protein contains aconserved phosphatase domain at residues 30-278 and is localized to thecytoplasmic face of the endoplasmic reticulum by its C-terminal 35residues. Its interactions with other proteins are mediated byproline-rich regions and SH2 compatible sequence. PTP1B is believed toact as a negative regulator in insulin signaling.

McGuire et al. (Diabetes 1991, 40, 939), demonstrated that non-diabeticglucose intolerant subjects possessed significantly elevated levels ofPTP activity in muscle tissue vs. normal subjects, and that insulininfusion failed to suppress PTP activity as it did in insulin sensitivesubjects.

Meyerovitch et al (J. Clinical Invest. 1989, 84, 976) observedsignificantly increased PTP activity in the livers of two rodent modelsof IDDM, the genetically diabetic BB rat, and the STZ-induced diabeticrat. Sredy et al (Metabolism, 44, 1074, 1995) observed similar increasedPTP activity in the livers of obese, diabetic ob/ob mice, a geneticrodent model of NIDDM.

Zhang et al (Curr. Opin. Chem. Biol., 5(4), p.416-23 (English) 2001)mentioned that PTPs are also implicated in a wide variety of otherdisorders, including cancer. Bjorge, J. D et al. (J. Biol. Chem.,275(52), p.41439-41446 (English) 2000) indicate that PTP1B is theprimary protein-tyrosine phosphatase capable of dephosphorylating c-Srcin several human breast cancer cell lines and suggests a regulatory rolefor PTP1B in the control of c-Src kinase activity.

Pathre et al (J. Neurosci. Res., 63(2), p.143-150 (English) 2001)describes that PTP1B regulates neurite extension mediated by cell-celland cell-matrix adhesion molecules. Further, Shock L. P et al (Mol.Brain. Res., 28(1), p.110-16 (English) 1995) demonstrates that adistinct overlapping set of PTPs is expressed in the developing brainand retinal Mueller glia, including 2 novel PTPs that may participate inneural cell communication.

The insulin receptor (IR) is a prototypical tyrosine kinase receptorwhose ligand binding and dimerization results in auto-phosphorylation onmultiple tyrosines. This is followed by the recruitment andphosphorylation of IRS1-4 (depending on the tissue) and P13K Althoughvanadium-containing compounds have been known since the 19^(th) centuryto alleviate diabetes, it was understood only recently that theseinhibitors stimulate the insulin signaling pathway by blocking PTPaction. Evidence for the involvement of the IR (insulin receptor) andIRS-1 in this phenotype was that both proteins show increased tyrosinephosphorylation in the PTP1B-mutated mice. The available data stronglysuggest that in particular PTP1B is a promising target for thedevelopment of drugs to treat diabetes and obesity (Brian P. Kennedy andChidambaram Ramachandran; Protein Tyrosine Phosphatase-1B in Diabetes;Biochemical Pharmacology, Vol. 60, pp. 877-883, 2000).

The compounds of this invention turned out to be inhibitors of PTPs.They are particularly useful in the treatment and/or prevention ofmetabolic disorders mediated by insulin resistance or hyperglycemia,comprising diabetes type I and/or II, inadequate glucose tolerance,insulin resistance, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS). Inparticular the compounds of this invention are useful in the treatmentand/or prevention of diabetes type II.

SUMMARY OF THE INVENTION

The invention therefore relates to the use of oxindole hydrazidederivatives of formula (I) for the treatment and/or prevention ofmetabolic disorders mediated by insulin resistance or hyperglycemia,comprising diabetes type I and/or II, inadequate glucose tolerance,insulin resistance, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS)

wherein X, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, m, n and p are defined indetail in the description below.

The invention further relates to the use of oxindole hydrazides asmedicament and the use of oxindoel hydrazide derivatives to modulate,notably to inhibit the activity of PTPs, in particular of PTP1B, TC-PTP,SHP and GLEPP-1. The present invention is furthermore related to noveloxindole hydrazide derivatives and a method of preparing them.

DESCRIPTION OF THE INVENTION

The following paragraphs provide definitions of the various chemicalmoieties that make up the compounds according to the invention and areintended to apply uniformly through-out the specification and claimsunless an otherwise expressly set out definition provides a broaderdefinition.

“PTPs” are protein tyrosine phosphatases and include for instance PTP1B,TC-PTP, PTP-β, DEP-1, LAR, SHP-1, SHP-2, GLEPP-1, PTP-κ, PTP-μ, VHR,hVH5, LMW-PTP, PTEN.

“Aryl” refers to an unsaturated aromatic carbocyclic group of from 6 to14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl). Specific aryl include phenyl,naphthyl, phenantrenyl and the like.

“C₁-C₆-alkyl aryl” refers to C₁-C₆-alkyl groups having an arylsubstituent, including benzyl phenethyl and the like.

“Heteroaryl” refers to a monocyclic heteroaromatic, or a bicyclic or atricyclic fused-ring heteroaromatic group. Particular examples ofheteroaromatic groups include optionally substituted pyridyl, pyrrolyl,furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, 1,2,4oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl,[2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,imidazo[1,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,pyrido[3,4-b]pyridyl, pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl or benzoquinolyl.

“C₁-C₆-alkyl heteroaryl” refers to C₁-C₆-alkyl groups having aheteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl,2-(1H-indol-3-yl)ethyl and the like.

“Alkanoic acid” refers to monovalent alkyl groups having from 1-6 carbonatoms and comprising a carboxyl group —COOH as functional group e.g.methanoic acid, ethanoic acid or propanoic acid.

“Alkenyl” refers to alkenyl groups preferably having from 2 to 6 carbonatoms and having at least 1 or 2 sites of alkenyl unsaturation. Specificalkenyl groups include ethenyl (—CH═CH₂), n-2-propenyl (allyl,—CH₂CH═CH₂) and the like.

“C₂-C₆-alkenyl aryl” refers to C₂-C₆-alkenyl groups having an arylsubstituent, including 2-phenylvinyl and the like.

“C₂-C₆-alkenyl heteroaryl” refers to C₂-C₆-alkenyl groups having aheteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.

“Alkynyl” refers to alkynyl groups preferably having from 2 to 6 carbonatoms and having at least 1-2 sites of alkynyl unsaturation, specificalkynyl groups include ethynyl (-C≡H), propargyl (—CH₂C≡CH), and thelike.

“C₂-C₆-alkynyl aryl” refers to C₂-C₆-alkynyl groups having an arylsubstituent, including phenylethynyl and the like.

“C₂-C₆-alkynyl heteroaryl” refers to C₂-C₆-alkynyl groups having aheteroaryl substituent, including 2-thienylethynyl and the like.

“C₃-C₈-cycloalkyl” refers to a saturated carbocyclic group of from 3 to8 carbon atoms having a single ring (e.g., cyclohexyl) or multiplecondensed rings (e.g., norbornyl). Specific cycloalkyl includecyclopentyl, cyclohexyl, norbornyl and the like.

“C₁-C₆-alkyl cycloalkyl” refers to C₁-C₆-alkyl groups having acycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl,and the like.

“Heterocycloalkyl” refers to a C₃-C₈-cycloalkyl group according to thedefinition above, in which 1 to 3 carbon atoms are replaced byheteroatoms chosen from the group consisting of O, S, NR, R beingdefined as hydrogen or C₁-C₆ alkyl. Specific heterocycloalkyl includepyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, andthe like.

“C₁-C₆-alkyl heterocycloalkyl” refers to C₁-C₆-alkyl groups having aheterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl,4-morpholinylmethyl, (1-methyl-4-piperidinyl)methyl and the like.

“Carboxy” refers to the group —C(O)OH.

“C₁-C₆-alkyl carboxy” refers to C₁-C₆-alkyl groups having a carboxysubstituent, including 2-carboxyethyl and the like.

“Acyl” refers to the group —C(O)R where R includes H, “C₁-C₆-alkyl”,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,heterocycloalkyl“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkylaryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl acyl” refers to C₁-C₆-alkyl groups having an acylsubstituent, including 2-acetylethyl and the like.

“Aryl acyl” refers to aryl groups having an acyl substituent, including2-acetylphenyl and the like.

“Heteroaryl acyl” refers to hetereoaryl groups having an acylsubstituent, including 2-acetylpyridyl and the like.

“C₃-C₈-(hetero)cycloalkyl acyl” refers to 3 to 8 membered cycloalkyl orheterocycloalkyl groups having an acyl substituent.

“Acyloxy” refers to the group —OC(O)R where R includes H, “C₁-C₆-alkyl”,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl acyloxy” refers to C₁-C₆-alkyl groups having an acyloxysubstituent, including 2-(acetyloxy)ethyl and the like.

“Alkoxy” refers to the group —O—R where R includes “C₁-C₆-alkyl”,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl alkoxy” refers to C₁-C₆-alkyl groups having an alkoxysubstituent, including 2-ethoxyethyl and the like.

“Alkoxycarbonyl” refers to the group —C(O)OR where R includes“C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl alkoxycarbonyl” refers to C₁-C₆-alkyl groups having analkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and thelike.

“Aminocarbonyl” refers to the group —C(O)NRR′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl aminocarbonyl” refers to C₁-C₆-alkyl groups having anaminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl andthe like.

“Acylamino” refers to the group —NR(CO)R′ where each R, R′ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl acylamino” refers to C₁-C₆-alkyl groups having an acylaminosubstituent, including 2propionylamino)ethyl and the like.

“Ureido” refers to the group —NRC(O)NR′R″ where each R, R′, R″ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”, and where R′ and R″, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl ureido” refers to C₁-C₆-alkyl groups having an ureidosubstituent, including 2-(N′-methylureido)ethyl and the like.

“Carbamate” refers to the group —NRC(O)OR′ where each R, R′ isindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“Amino” refers to the group —NRR′ where each R, R′ is independentlyhydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”, and where R and R′, together with the nitrogen atomto which they are attached, can optionally form a 3-8-memberedheterocycloalkyl ring.

“C₁-C₆-alkyl amino” refers to C₁-C₆-alkyl groups having an aminosubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Ammonium” refers to a positively charged group —N⁺RR′R″, where each R,R′,R″ is independently, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”, and where Rand R′, together with the nitrogen atom to which they are attached, canoptionally form a 3-8-membered heterocycloalkyl ring.

“C₁-C₆-alkyl ammonium” refers to C₁-C₆-alkyl groups having an ammoniumsubstituent, including 2-(1-pyrrolidinyl)ethyl and the like.

“Halogen” refers to fluoro, chloro, bromo and iodo atoms.

“Sulfonyloxy” refers to a group —OSO₂—R wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an—OSO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl sulfonyloxy” refers to C₁-C₆-alkyl groups having asulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and thelike.

“Sulfonyl” refers to group “—SO₂—R” wherein R is selected from H,“aryl”, “heteroaryl”, “C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted withhalogens, e.g., an —SO₂—CF₃ group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl sulfonyl” refers to C₁-C₆-alkyl groups having a sulfonylsubstituent, including 2-(methylsulfonyl)ethyl and the like.

“Sulfinyl” refers to a group “—S(O)—R” wherein R is selected from H,“C₁-C₆-alkyl”, “C₁-C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃group, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”.

“C₁-C₆-alkyl sulfinyl” refers to C₁-C₆-alkyl groups having a sulfinylsubstituent, including 2-(methylsulfinyl)ethyl and the like.

“Sulfanyl” refers to groups —S—R where R includes H, “C₁-C₆-alkyl”,“C₁-C₆-alkyl” substituted with halogens, e.g., an —SO—CF₃ group,“C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”, “C₃-C₈-cycloalkyl”,“heterocycloalkyl”, “aryl”, “heteroaryl”, “C₁-C₆-alkyl aryl” or“C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”, “C₂-C₆-alkenylheteroaryl”, “C₂-C₆-alkynyl aryl”, “C₂-C₆-alkynylheteroaryl”,“C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkyl heterocycloalkyl”. Specificsulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

“C₁-C₆-alkyl sulfanyl” refers to C₁-C₆-alkyl groups having a sulfanylsubstituent, including 2-(ethylsulfanyl)ethyl and the like.

“Sulfonylamino” refers to a group —NRSO₂—R′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl sulfonylamino” refers to C₁-C₆-alkyl groups having asulfonylamino substituent, including 2-(ethylsulfonylamino)ethyl and thelike.

“Aminosulfonyl” refers to a group —SO₂—NRR′ where each R, R′ includesindependently hydrogen, “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”, “C₂-C₆-alkynyl”,“C₃-C₈-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”,“C₁-C₆-alkyl aryl” or “C₁-C₆-alkyl heteroaryl”, “C₂-C₆-alkenyl aryl”,“C₂-C₆-alkenyl heteroaryl”, “C₂-C₆-alkynyl aryl”,“C₂-C₆-alkynylheteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”.

“C₁-C₆-alkyl aminosulfonyl” refers to C₁-C₆-alkyl groups having anaminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyland the like.

“Substituted or unsubstituted”: Unless otherwise constrained by thedefinition of the individual substituent, the above set out groups, maybe substituted by moieties including “nitro”, “hydroxy”, “halogen”,“carboxy”, “amino” or groups such as “alkyl” (e.g.“trihalomethyl”),“alkenyl”, “alkynyl”, “aryl” “cycloalkyl” and “heteroaryl”. Said groupscan optionally be substituted with from 1 to 5 substituents selectedfrom the group consisting of “C₁-C₆-alkyl”, “C₂-C₆-alkenyl”,“C₂-C₆-alkynyl”, “cycloalkyl”, “heterocycloalkyl”, “C₁-C₆-alkyl aryl”,“C₁-C₆-alkyl heteroaryl”, “C₁-C₆-alkyl cycloalkyl”, “C₁-C₆-alkylheterocycloalkyl”, “amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”,“aminocarbonyl”, “alkoxycarbonyl”, “ureido”, “aryl”, “carbamate”,“heteroaryl”, “sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”,“carboxy”, trihalomethyl, cyano, hydroxy, mercapto, nitro, and the likeAlternatively said substitution could also comprise situations whereneighboring substituents have undergone ring closure, notably whenviccinal functional substituents are involved, thus forming e.g.lactams, lac-tons, cyclic anhydrides, but also acetals, thioacetals,aminals formed by ring closure for instance in an effort to obtain aprotective group.

“Pharmaceutically acceptable salts or complexes” refers to salts orcomplexes of the below-identified compounds of formula (I) that retainthe desired biological activity. Examples of such salts include, but arenot restricted to acid addition salts formed with inorganic acids (e.g.hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid,pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid,naphthalene disulfonic acid, and poly-galacturonic acid. Said compoundscan also be administered as pharmaceutically acceptable quaternary saltsknown by a person skilled in the art, which specifically include thequarternary ammonium salt of the formula —NR,R′,R″⁺ Z⁻, wherein R, R′,R″ is independently hydrogen, alkyl, or benzyl, and Z is a counterion,including chloride, bromide, iodide, —O-alkyl, toluenesulfonate,methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate,succinate, acetate, glycolate, maleate, malate, fumarate, citrate,tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).

“Pharmaceutically active derivative” refers to any compound that uponadministration to the recipient, is capable of providing directly orindirectly, the activity disclosed herein.

“Enantiomeric excess” (ee) refers to the products that are obtained byan asymmetric synthesis, i.e. a synthesis involving non-racemic startingmaterials and/or reagents or a synthesis comprising at least oneenantioselective step, whereby a surplus of one enantiomer in the orderof at least about 52% ee is yielded. In the absence of an asymmetricsynthesis, racemic products are usually obtained that do however alsohave the inventive set out activity as PTP inhibitors.

Said formula also comprises its tautomers, its geometrical isomers, itsoptically active forms as enantiomers, diastereomers and its racemateforms, as well as pharmaceutically acceptable salts thereof. Specificpharmaceutically acceptable salts of the formula (I), are acid additionsalts formed with pharmaceutically acceptable acids like hydrochloride,hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate,acetate, benzoate, succinate, fumarate, maleate, lactate, citrate,tartrate, gluconate, methanesulfonate, benzenesulfonate, andpara-toluenesulfonate salts.

A first aspect of the present invention consists in the use of compoundsof formula (I):

as well as its tautomers, geometrical isomers, its optically activeforms as enantiomers, diastereomers and its racemate forms, as well aspharmaceutically acceptable salts thereof, for the preparation ofpharmaceutical compositions for the treatment and/or prevention ofmetabolic disorders mediated by insulin resistance or hyperglycemia,comprising diabetes type I and/or II, inadequate glucose tolerance,insulin resistance, hyperlipidemia, hypercholesterolemia, obesity andpoycystic ovary syndrome (PCOS).

In formula I the substituents are as follows:

-   R¹ is either halogen or —(C═O)N—(C₆-C₁₈)-alkyl, d is 1 to 4. In a    further embodiment d is 1 or 2, in particular 1.-   R² is selected from the group consisting of H, —CO—NH—R or    —(CH₂)_(u)—CO—OR wherein u is an integer from 1 to 7, R is H or    substituted or unsubstituted (C₁-C₆)alkyl (thus giving a R² being    e.g. a methyl methanoate, -ethanoate, -propanoate, -butanoate,    -pentanoate or -hexanoate group). In one embodiment R² is H.-   R³ is selected from the group comprising or consisting of H or    substituted or unsubstituted C₁-C₆ alkyl. In one embodiment R²    and/or R³ is H.-   R⁴, R⁵, R⁶ and R⁷ are each independently from each other selected    from the group consisting of H, halogen, —NO₂, —OH, substituted or    unsubstituted (C₁-C₆)-alkyl, substituted or unsubstituted 3-8    membered cycloalkyl, substituted or unsubstituted 3-8 membered    heterocycloalkyl which may contain 1-2 further heteroatoms selected    from O, N or S, substituted or unsubstituted    (C₁-C₆)-alkyl-heterocycloalkyl wherein said heterocycloalkyl may    contain 1-2 further heteroatoms selected from O, N or S, substituted    or unsubstituted aryl, substituted or unsubstituted    (C₁-C₆)-alkyl-aryl, substituted or unsubstituted heteroaryl,    substituted or unsubstituted (C₁-C₆)alkyl-heteroaryl. In one    embodiment R⁴, R⁵, R⁶ and R⁷ are H or substituted or unsubstituted    alkyl groups, like methyl or ethyl groups. According to a specific    embodiment, all of R⁴, R⁵, R⁶ and R⁷ are H.-   R⁸ is selected from the group comprising or consisting of H,    halogen, hydroxy, acyl, amino, carboxy, cyano, nitro, an    unsubstituted or substituted C₁-C₆-alkyl, an unsubstituted or    substituted C₂-C₆-alkenyl, an unsubstituted or substituted    C₂-C₆-alkynyl, an unsubstituted or substituted C₁-C₆-alkyl carboxy,    an unsubstituted or substituted C₁-C₆-alkyl acyl, an unsubstituted    or substituted C₁-C₆-allyl alkoxycarbonyl, an unsubstituted or    substituted aminocarbonyl, an unsubstituted or substituted    carbonylamino, an unsubstituted or substituted C₁-C₆-alkyl    aminocarbonyl, an unsubstituted or substituted hydrazinocarbonyl, an    unsubstituted or substituted C₁-C₆-alkyl acyloxy, acylamino, an    unsubstituted or substituted C₁-C₆-alkyl acylamino, ureido, an    unsubstituted or substituted C₁-C₆-alkyl ureido, an unsubstituted or    substituted C₁-C₆-alkyl carbamate, an unsubstituted or substituted    C₁-C₆-alkyl amino, C₁-C₆ alkoxy, an unsubstituted or substituted    C₁-C₆-alkyl alkoxy, sulfanyl, an unsubstituted or substituted    C₁-C₆-alkyl sulfanyl, sulfinyl, an unsubstituted or substituted    C₁-C₆-alkyl sulfinyl, sulfonyl, sulfonylamino, an unsubstituted or    substituted C₁-C₆-alkyl sulfonyl, an unsubstituted or substituted    C₁-C₆-alkyl sulfonylaminoaryl, substituted or unsubstituted aryl,    substituted or unsubstituted heteroaryl, an unsubstituted or    substituted C₃-C₈-cycloalkyl or heterocycloalkyl, an unsubstituted    or substituted C₁-C₆-alkyl aryl, an unsubstituted or substituted    C₁-C₆-alkyl heteroaryl, an unsubstituted or substituted    C₂-C₆-alkenyl-aryl or -heteroaryl, an unsubstituted or substituted    C₂-C₆-alkynyl aryl or -heteroaryl.

In one embodiment R⁸ is selected from the group consisting of H,halogen, cyano, substituted or unsubstituted (C₁-C₆)alkyl (e.g. —CF₃ or(C₁-C₆)-alkanoic acid or ester), substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —SO—R⁹, —SO—R⁹, substituted orunsubstituted (C₁-C₆)alkyl-SO₂—R⁹, —NO₂, —N(R)₂, substituted orunsubstituted (C₁-C₆)alkyl-O—R^(9, —SR) ⁹, —(C═O)O—R⁹, —(C═O)—R⁹,—(C═O)N(R⁹)₂, —(C═O)NH—R⁹, —(C═O)NR⁹—N(R⁹)₂, —NR⁹—(C═O)—N(R⁹)₂,—NR⁹—(SO₂—R⁹), —NH—(C═O)—R⁹, substituted or unsubstituted(C₁-C₆)-alkyl-NH—(C═O)—R⁹, —NR⁹—(C═O)—R⁹ wherein R⁹ is selected from thegroup consisting of H, substituted or unsubstituted (C₁-C₆)-alkyl,substituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted 3-8 membered heterocycloalkyl which may contain 1-2further heteroatoms selected from O, N or S, substituted orunsubstituted (C₁-C₆)-alkyl-heterocycloalkyl wherein saidheterocycloalkyl may contain 1-2 further heteroatoms selected from O, Nor S, substituted or unsubstituted aryl, substituted or unsubstituted(C₁-C₆)-alkyl-aryl, substituted or unsubstituted (C₁-C₆)-alkoxy-aryl,substituted or unsubstituted heteroaryl, substituted or unsubstituted(C₁-C₆)-alkyl-heteroaryl or substituted or unsubstituted(C₁-C₆)-alkoxy-heteroaryl, substituted or unsubstituted(C₁-C₆)-alkyl-COOR¹⁰ wherein R¹⁰ is H or substituted or unsubstituted(C₁-C₆)alkyl or —NH₂.

A is selected from the group consisting of a bond, —O—, —S—, —SO—,—SO₂—, amino, urea, sulfonylamino or acylamino;

In one embodiment A is a bond or O.

B is selected from the group consisting of substituted or unsubstitutedarylene, substituted or unsubstituted heteroarylene, substituted orunsubstituted heterocycloalkylene or substituted or unsubstitutedcycloalkylene.

X is C, S or SO.

m, n and p are each independently from each other an integer from 0 to6. In one embodiment m is 0, 1 or 2, while n is 0 or 1. In a furtherembodiment p is 1 or 2. In still a further embodiment p is 1.

Examples of B include optionally substituted phenyl, naphthyl,phenantrenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl,[1,3]thiazolo[3,2-b][1,2,4]triazolyl, carbazolyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,3-oxadiazolyl, benzo(2,1,3)oxadiazolyl,benzo(1,2,5)oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl,benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryl, benzothienyl,benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl,benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridazinyl, pyrimidyl,quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl,napthyridinyl, quinolyl, isoquinolyl, tetrazolyl,5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl,pteridinyl, carbazolyl, xanthenyl, benzoquinolyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, oxolanyl,pyrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, pyridyl,imidazolidinyl, 1,2,4-oxadiazolidinyl, 1,2,5-oxadiazolidinyl,1,3,4-oxadiazolidinyl, isoxazolidinyl or morpholinyl.

According to one embodiment B is selected from the group consisting ofphenyl, biphenyl, benzo(1,2,5)oxadiazolyl, furyl, thiadiazolyl, thienyl,thiazolyl, indolyl, piperidinyl, tetrazolyl, 1,2,3-triazolyl,1,2,4-triazolyl and pyridyl.

According to a further embodiment, B is a substituted or anunsubstituted phenyl.

According to a further embodiment, R¹ is Br or I and d is 1.

The substituents R⁴, R⁵, R⁶ and R⁷ in—one embodiment—are independentlyfrom each other selected from the group consisting of H and substitutedor unsubstituted (C₁-C₆)-alkyl.

Still a further embodiment comprises oxindoles of formula I wherein nand m are each 0, A is a bond, B is a substituted or unsubstitutedphenyl, p is 1 and R⁸ is —NH—CO—(C₁-C₆-alkyl)-Ar₁ or —O—Ar₁ wherein Ar₁is a substituted or unsubstituted phenyl group.

A further aspect of the present invention is related to the use ofoxindole hydrazide derivatives of formula (Ia)

wherein m′ is 0 or 1 and R⁸ is selected from the group consisting of H,halogen, cyano, substituted or unsubstituted (C₁-C₆)alkyl (e.g. a —CF₃moiety or a (C₁-C₆)-alkanoic acid or ester), —SR⁹, —SO—R⁹, —SO₂—R⁹,substituted or unsubstituted aryl , substituted or unsubstitutedheteroaryl, substituted or unsubstituted (C₁-C₆)alkyl-SO₂—R⁹, —NO₂,—N(R⁹)₂, —O—R⁹, (C₁-C₆)alkyl-OR⁹, —(C═O)O—R⁹, —(C═O)—R⁹, —(C═O)N(R⁹)₂,—(C═O)NHR⁹, —(C═O)NR⁹—N(R⁹)₂, —N—(C═O)—R⁹, —NR⁹—(C═O)—N(R⁹)₂,—NR⁹—(SO₂—R⁹), —NH—(C═O)—R⁹, (C₁-C₆)alkyl-NH(C═O)—R⁹ or —NR⁹—(C═O)—R⁹and where R⁹ is as above defined, for the preparation of apharmaceutical composition for the treatment and/or prevention ofmetabolic disorders mediated by insulin resistance or hyperglycemia,comprising diabetes type I and/or II, inadequate glucose tolerance,insulin resistance, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, obesity, polycystic ovary syndrome (PCOS).

In a further embodiment of the invention, R⁸ is —NO₂ or —COOR⁹ whereinR⁹ is as above defined.

Specifically, the compounds according to formula (I) and (Ia) aresuitable for the modulation of the activity of PTPs, in particular ofPTP1B, TC-PTP, SHP and GLEPP-1. It is assumed that the compounds of thepresent invention are therefore useful for the treatment and/orprevention of disorders which are mediated by FTPs, in particular ofPTP1B, TC-PTP, SHP and GLEPP-1. Said treatment involves themodulation—notably the down regulation or the inhibition—of PTPs,particularly of PTP1B, TC-PTP, SHP and GLEPP-1 and more particularlyPTP1B.

More specifically, compounds according to formula (I) and (Ia) areparticularly useful for the treatment and/or prevention of diabetes typeII.

A further aspect of the present invention is related to novel compoundsof the following formula (II)

wherein m′ is as above-defined and p is an integer from 1 to 3.

A is O, or a bond, B is selected from the group consisting ofsubstituted or unsubstituted arylene, substituted or unsubstitutedheteroarylene, substituted or unsubstituted heterocycloalkylene orsubstituted or unsubstituted cycloalkylene, further B is substituted orunsubstituted a phenyl group.

R⁸ is selected from the group consisting of is selected from the groupcomprising or consisting of H, halogen, hydroxy, acyl, amino, carboxy,cyano, nitro, an unsubstituted or substituted C₁-C₆-alkyl, anunsubstituted or substituted C₂-C₆-alkenyl, an unsubstituted orsubstituted C₂-C₆-alkynyl, an unsubstituted or substituted C₁-C₆-alkylcarboxy, an unsubstituted or substituted C₁-C₆-alkyl acyl, anunsubstituted or substituted C₁-C₆-alkyl alkoxycarbonyl, anunsubstituted or substituted C₁-C₆-alkyl aminocarbonyl, an unsubstitutedor substituted C₁-C₆-alkyl acyloxy, acylamino, an unsubstituted orsubstituted C₁-C₆-alkyl acylamino, ureido, an unsubstituted orsubstituted C₁-C₆-alkyl ureido, an unsubstituted or substitutedC₁-C₆-alkyl carbamate, an unsubstituted or substituted C₁-C₆-alkylamino, C₁-C₆ alkoxy, an unsubstituted or substituted C₁-C₆-alkyl alkoxy,sulfanyl, an unsubstituted or substituted C₁-C₆-alkyl sulfanyl,sulfinyl, an unsubstituted or substituted C₁-C₆-alkyl sulfinyl,sulfonyl, sulfonylamino, an unsubstituted or substituted C₁-C₆-alkylsulfonyl, an unsubstituted or substituted C₁-C₆-alkyl sulfonylaminoaryl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, an unsubstituted or substituted C₃-C₈-cycloalkyl orheterocycloalkyl, an unsubstituted or substituted C₁-C₆-alkyl aryl, anunsubstituted or substituted C₁-C₆-alkyl heteroaryl, an unsubstituted orsubstituted C₂-C₆-alkenyl-aryl or -heteroaryl, an unsubstituted orsubstituted C₂-C₆-alkynyl aryl or -heteroaryl.

The Formula (II) does not include the following seven compounds, though:

Compounds a), b), e), f) and g) are commercially available fromcatalogues of ChemDiv. Inc., AsInEx and SPECS and BioSPECS and representcompounds having so far not been described as having any therapeuticutility. Compounds c) and d) are specifically disclosed in Egypt. J.Pharm. Sci., 14(1) English) 1973.

In one embodiment R⁸ is selected from the group consisting of H,halogen, cyano, substituted or unsubstituted (C₁-C₆)alkyl (e.g. —CF₃ or(C₁-C₆)-alkanoic acid or ester), substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, —SO—R⁹, —SO₂—R⁹,(C₁-C₆)alkyl-SO₂—R⁹, —NO₂, —N(R⁹)₂, (C₁-C₆)-alkyl-O—R⁹, —SR⁹, —SO₂—R⁹,—(C═O)O—R⁹, —(C═O)—R⁹, —(C═O)N(R⁹)₂, —(C═O)NH—R⁹, —(C═O)NR⁹—N(R⁹)₂,—NR⁹—(C═O)—N(R⁹)₂, —NR⁹—(SO₂—R⁹), —NH—(C═O)—R⁹,(C₁-C₆)-alkyl—NH—(C═O)—R⁹, —NR⁹—(C═O)—R⁹ wherein R⁹ is as above-defined.

In a specific embodiment of the invention, m′ is 0, p is 0 or 1, A is abond or O, B is a substituted or unsubstituted phenyl group and R⁸ isselected in the group consisting of—NO₂, —CO₂—R⁹ and —NH—(C═O)—R⁹wherein R⁹ is as above defined.

Novel compounds of Formula II are in particular those of the groupconsisting of:

-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide-   3,5-Dichloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methylbenzohydrazide-   4-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   3-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-nitrobenzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-phenoxybenzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(trifluoromethyl)benzohydrazide-   4-tert-butyl-N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)[1,1′-biphenyl]-4-carbohydrazide-   4-Bromo-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-nitrobenzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methoxybenzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-methoxybenzohydrazide-   4-Amino-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   4-(Dimethylamino)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4-nitrophenoxy)acetohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(trifluoromethoxy)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,1,3-benzoxadiazole-5-carbohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-(5-nitro-(2-furohydrazide))-   Methyl    4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoate-   Methyl    4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate-   4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoic    acid-   4-Iodo-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-phenoxybenzohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4-iodophenoxy)acetohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[(4-methylphenyl)sulfonyl]acetohydrazide-   2-{[(2-Furylmethyl)sulfonyl]methyl}-N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4-carbohydrazide-   2-Hydroxy-N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N-(2-Furylmethyl)-N′-{2-[2-5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}urea-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(methylsulfanyl)benzohydrazide-   Methyl    6-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}nicotinate-   Benzyl    4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-furamide-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)hexanamide-   4-Cyano-N-(4{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide-   4-(Hexyloxy)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide-   4-Heptyl-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide-   2-{2-Nitro-4,5-dimethoxyphenyl}-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-yliden)acetohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1-(3-pyridinylmethyl)-4-piperidinecarbohydrazide-   2-Amino-5-nitro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   2-[5-(3-Nitrophenyl)-2H-tetrazol-2-yl]-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(1-pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide-   4-{2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoic    acid-   4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-phenylbenzamide-   4-Cyano-N-(3-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide-   N′-[5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-4-[4-(4-morpholinylmethyl)    phenoxy]benzohydrazide-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)    benzamide-   4-(Benzyloxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N-(3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide-   4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide-   4-Chloro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)benzamide-   Methyl    4-{3-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzoate-   2-[(2-Chlorophenoxy)methyl]-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4-carbohydrazide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazol-6-yl)acetohydrazide-   4-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]butanohydrazide-   2-{[3-Chloro-5-trifluoromethyl)-2-pyridinyl]amino}-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide-   1-Benzoyl-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-piperidinecarbohydrazide-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-phenoxyacetamide-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-nicotinamide-   3-Nitro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-benzyl)benzamide-   N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)[1,1′-biphenyl]-4-carboxamide-   Methyl-3-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate-   Methyl    4-{[[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino](oxo)acetyl]-amino}benzoate-   3-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}phenyl)propanamide-   4-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoyl)-amino]benzoic    acid-   3-(3,4-Dihydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide-   3-(3-Hydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)propanamide-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-6-methoxy-5-nitronicotinohydrazide-   3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]sulfonyl}benzoic    acid-   2-Hydroxy-5-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]sulfonyl}-benzoic    acid-   N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-5-(2-pyridinyl)-2-thiophenesulfono-hydrazide-   4-Chloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-nitrobenzenesulfono-hydrazide-   Methyl    {3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate-   N-Dodecyl-3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indole-1-carboxamide-   Methyl    (3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate

Further novel compounds falling into Formula (I) are selected from thegroup consisting of:

-   4-Nitro-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   Methyl    4-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate-   4-Methoxy-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide-   N-(4-{[2-(5-Bromo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide-   N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-{3-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzohydrazide-   N-(4-{[2-(5-Bromo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-phenoxyacetamide-   N-(4-{[2-(5-Bromo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)-3-nitrobenzamide-   Methyl    3-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate-   N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[4-(1H-tetrazol-5-yl)phenoxy]-acetohydrazide-   (3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic    acid-   (3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic    acid, tromethanine (2-amino-2-hydroxymethyl-1,3-propanediol) salt-   (3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   2-(4-cyanophenoxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide-   4-({2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}thio)-3-nitrobenzenesulfonamide-   N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-N-methyl-3-phenylpropanamide-   methyl    {3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate-   methyl    4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-4-oxobutanoate-   3-(1,3-benzodioxol-5-yl)-N-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}phenyl)propanamide-   {3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2oxo-2,3-dihydro-1H-indol-1-yl}acetic    acid-   {3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   methyl    6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-6-oxohexanoate-   methyl    4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]carbonyl}benzoate-   methyl    8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-8-oxooctanoate-   methyl    5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-5-oxopentanoate-   8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-8-oxooctanoic    acid-   8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-8-oxooctanoic    acid,N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-6-oxohexanoic    acid-   6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-6-oxohexanoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-4-oxobutanoic    acid-   4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-4-oxobutanoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-5-oxopentanoic    acid-   5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-5-oxopentanoic    acid N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]carbonyl}benzoic    acid-   4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]carbonyl}benzoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)-glucitol) salt-   methyl    4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-benzyl)amino]carbonyl}benzoate-   4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)-amino]carbonyl}benzoic    acid-   4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)-amino]carbonyl}benzoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   benzyl    (2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenoxy)-3-phenylpropanoate-   (2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenoxy)-3-phenylpropanoic    acid-   (2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenoxy)-3-phenylpropanoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   methyl    4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoate-   4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoic    acid-   4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoic    acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt-   methyl    3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate-   3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]sulfonyl}phenyl)    propanoic acid-   3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]sulfonyl}phenyl)    propanoic acid, N-methyl-D-glucamine    (1-deoxy-1-(methylamino)glucitol) salt-   N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(1H-tetrazol-5-yl)benzohydrazide

A further aspect of the present invention is related to the use ofoxindole hydrazide derivatives according to formula II as a medicamentin particular for the preparation of pharmaceutical compositions for thetreatment and/or prevention of metabolic disorders mediated by insulinresistance or hyperglycemia, comprising diabetes type I and/or II,inadequate glucose tolerance, insulin resistance, hyperlipidemia,hypertriglyceridemia, hypercholesterolemia, obesity, polycystic ovarysyndrome (PCOS).

Specific compounds according to formula (II) are suitable for themodulation of the activity of PTPs, in particular of PTP1B, TC-PTP, SHPand GLEPP-1. It is assumed that the compounds of the present inventionare therefore useful for the treatment and/or prevention of disorderswhich are mediated by PTPs, in particular of PTP1B, TC-PTP, SHP andGLEPP-1. Said treatment involves the modulation—notably the downregulation or the inhibition—of PTPs, particularly of PTP1B, TC-PTP, SHPand GLEPP-1 and more particularly PTP1B.

More specifically, the compounds of the present invention according toformula (II) are particularly useful for the treatment and/or preventionof diabetes II.

The oxindole hydrazide derivatives exemplified in this invention may beprepared from readily available starting materials using the followinggeneral methods and procedures. It will be appreciated that wheretypical or other experimental conditions (i.e. reaction temperatures,time, moles of reagents, solvents, etc.) are given, other experimentalconditions can also be used unless otherwise stated. Optimum reactionconditions may vary with the particular reactants or solvents used, butsuch conditions can be determined by one skilled in the art by routineoptimisation procedures.

In general, the oxindole hydrazide derivatives according to formula (I)of this invention may be prepared from readily available startingmaterials. If such starting materials is not commercially available, itmay be prepared by standard synthetic techniques. The following generalmethods and procedures described hereinafter in the Examples may beemployed to prepare compounds of formula (I).

It will be appreciated that where typical or specific experimentalconditions (i.e. reaction temperatures, time, moles of reagents,solvents, etc.) are given, other experimental conditions can also beused unless otherwise stated. Optimum reaction conditions may vary withthe particular reactants or solvent used, but such conditions can bedetermined by a person skilled in the art by routine optimisationprocedures.

Generally, oxindole hydrazide derivatives according to formula (I) maybe obtained by reacting an isatine derivative of formula (A) with ahydrazide of formula (B) in acetic acid, optionally being in solutionwith a suitable alcohol such as ethanol or methanol, for several hours,e.g. from 2 to 24 hours as outlined in Scheme 1. Specific conditionsinvolve the heating of the isatine of formula (A) with a hydrazide offormula (B) in acetic acid or in ethanol containing 2% acetic acidbetween 80 and 120° C. for 2 hours. The oxindole hydrazide derivativesof formula (I) could be obtained by deprotection of any of its protectedform, e.g. a protected form of the acid (such as a benzylester)according to procedures known by a person skilled in the art. For allthe protection, deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, 3^(rd) edition, John Wiley & Sons Inc., 1999 (NY).

The method of preparation of the oxindole hydrazide compounds of formula(I) according to the above protocol has the specific advantage of beingconvenient and economic in the sense that it involves only a fewchemical steps and typically involves small amounts of cheap solvents.In addition this method of preparation usually does not require anyfurther step of purification.

Specific conditions involve the heating of the isatine of formula (A)with a protected hydrazide of formula (I) in acetic acid at 100° C. fora few hours in the presence of TFA.

Another protection of hydrazide of formula (B) is PG being Boc. Thusprotected hydrazide of formula (B) can include highly substituted R⁸ andthe formation of compounds of formula (I) can be obtained in a“one-step” protocol.

The compounds of the present invention are those of formula (I) and/orits isomers such as (I′) and/or tautomers such as of formula (I″).

Compounds of formula (A) and (B) are either commercially availablecompounds or may be prepared by standard synthetic techniques ashereinafter described in the Examples.

Specific compounds of formula (B) where X is carbon, can be obtainedfrom the treatment of hydrazine and the ester derivative (C) in anappropriate solvent such as an alcohol, e.g. methanol, for a 2-15 hours,as outlined in Scheme 2. Typically, aromatic ester derivatives offormula (C) require about 15 hours at reflux in a suitable solvent suchas ethanol. Aliphatic ester derivatives of formula (C) require a longertime of reaction at rt. Specifically activated ester derivatives, suchas ester derivatives of formula (C) bearing a —CH₂—(O) spacer betweenthe ester and central aromatic (A), usually require a shorter time ofreaction at rt in a suitable solvent such as methanol. Compounds offormula (C) are either commercially available or may be prepared bystandard synthetic techniques as hereinafter described.

The preparation of compound of formula (B) either follow the descriptionof Scheme 2 or was achieved by standard synthetic techniques asdescribed carefully hereinafter in the following Examples.

wherein R is a C₁-C₆ alkyl

Novel intermediate compounds of formula (B) are selected from the groupconsisting of:

-   N-[4-(Hydrazinocarbonyl)phenyl]-3-phenylpropanamide-   Phenylmethyl-4-[(N-aminocarbamoyl)methoxy]benzoate-   N-[4-(Hydrazinocarbonyl)phenyl]-2-furamide-   N-[4-(Hydrazinocarbonyl)phenyl]hexanamide-   4-Cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide-   4-(Hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]benzamide-   4-Heptyl-N-[4-(hydrazinocarbonyl)phenyl]benzamide-   4-(2-Hydrazino-2-oxoethoxy)benzoic acid-   4-Cyano-N-[3-(hydrazinocarbonyl)phenyl]benzamide-   4-(Hydrazinocarbonyl-N-(3-[(trifluoromethyl)sulfonyl]phenyl)benzamide-   4-Chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide-   1-Benzoyl-4-piperidinecarbohydrazide-   N-[4-(Hydrazinocarbonyl)phenyl]-2-phenoxyacetamide-   N-[4-(Hydrazinocarbonyl)benzyl]-3-nitrobenzamide-   N-[4-(Hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide-   3-(1,3-Benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide-   4-{[4-(Hydrazinocarbonyl)benzoyl]amino}benzoic acid-   3-(3,4-Dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide-   N-[4-(Hydrazinocarbonyl)phenyl]-3-(3-hydroxyphenyl)propanamide-   N-[4-(Hydrazinocarbonyl)phenyl]-2-phenoxyacetamide-   N-[4-(Hydrazinocarbonyl)benzyl]-3-nitrobenzamide-   Methyl 3-(2-hydrazino-2-oxoethoxy)benzoate-   2-[4-(1H-Tetrazol-5-yl)phenoxy]acetohydrazide-   4-(Hydrazinocarbonyl)-N-phenylbenzamide-   4-[4-(Morpholinylmethyl)phenoxy]benzohydrazide-   4-(2-Hydrazinocarbonyl-ethyl)-benzoic acid methyl ester-   2-[4-(1H-Tetrazol-5-yl)phenoxy]acetohydrazide-   2-(4-Cyanophenoxy)acetohydrazide-   Methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate-   N-[4-(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide-   Methyl (5-iodo-2,3dioxo-2,3-dihydro-1H-indol-1-yl)acetate-   Methyl 4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate-   tert-Butyl    2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate-   tert-Butyl    2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate-   tert-Butyl    2-(4-{[4-methoxycarbonyl)benzoyl]amino}benzoyl)hydrazinecarboxylate-   tert-Butyl    2-{4-[(9-methoxy-9-oxononanoyl)amino]benzoyl}hydrazinecarboxylate-   tert-Butyl    2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate-   4-({[4-(Methoxycarbonyl)benzoyl]amino}methyl)benzoic acid-   tert-Butyl    2-[4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoyl]hydrazinecarboxylate-   tert-Butyl 2-(4-hydroxybenzoyl)hydrazinecarboxylate-   tert-Butyl    2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate-   Methyl 4-(5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)butanoate-   tert-Butyl    2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate

If the above set out general synthetic methods are not applicable forthe obtention of compounds of formula I, suitable methods of preparationknown by a person skilled in the art should be used.

When employed as pharmaceuticals, the oxindole hydrazide derivatives ofthe present invention are typically administered in the form of apharmaceutical composition. Hence, pharmaceutical compositionscomprising a compound of formula (I), (Ia), (II) and a pharmaceuticallyacceptable carrier, diluent or excipient therefore are also within thescope of the present invention. A person skilled in the art is aware ofa whole variety of such carrier, diluent or excipient compounds suitableto formulate a pharmaceutical composition. Also, the present inventionprovides compounds of formula (II) for use as a medicament. Theinvention provides compounds of formula (I), (Ia), (I) for use as PTPinhibitors, for the treatment or prevention of disorders mediated byPTs, in particular of PTP1B, TC-PTP, SHP and GLEPP-1 in mammals, notablyof humans, either alone or in combination with other medicaments, e.g.in combination with a further inhibitor of PTPs. Specifically, theoxindole hydrazide derivatives of the invention are useful in thetreatment and/or prevention of metabolic disorders mediated by insulinresistance or hyperglycemia, comprising diabetes type I and/or II,obesity, polycystic ovary syndrome (PCOS). Said compounds areparticularyl useful in the treatment of diabete type II.

The compounds of the invention, together with a conventionally employedadjuvant, carrier, diluent or excipient may be placed into the form ofpharmaceutical compositions and unit dosages thereof, and in such formmay be employed as solids, such as tablets or filled capsules, orliquids such as solutions, suspensions, emulsions, elixirs, or capsulesfilled with the same, all for oral use, or in the form of sterileinjectable solutions for parenteral (including subcutaneous use). Suchpharmaceutical compositions and unit dosage forms thereof may compriseingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

When employed as pharmaceuticals, the oxindole hydrazide derivatives ofthis invention are typically administered in the form of apharmaceutical composition. Such compositions can be prepared in amanner well known in the pharmaceutical art and comprise at least oneactive compound. Generally, the compounds of this invention areadministered in a pharmaceutically effective amount. The amount of thecompound actually administered will typically be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered, the age, weight, and response of the individualpatient, the severity of the patient's symptoms, and the like.

The pharmaceutical compositions of these inventions can be administeredby a variety of routes including oral, rectal, transdermal,subcutaneous, intravenous, intramuscular, and intranasal. Thecompositions for oral adminis-tration can take the form of bulk liquidsolutions or suspensions, or bulk powders. More commonly, however, thecompositions are presented in unit dosage forms to facilitate accuratedosing. The term “unit dosage forms” refers to physically discrete unitssuitable as unitary dosages for human subjects and other mammals, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect, in association with asuitable pharmaceutical excipient. Typical unit dosage forms includeprefilled, premeasured ampoules or syringes of the liquid compositionsor pills, tablets, capsules or the like in the case of solidcompositions. In such compositions, the oxindole hydrazide derivative isusually a minor component (from about 0.1 to about 50% by weight orpreferably from about 1 to about 40% by weight) with the remainder beingvarious vehicles or carriers and processing aids helpful for forming thedesired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatine; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As above mentioned, the oxindole hydrazide derivatives offormula (I) in such compositions is typically a minor component,frequently ranging between 0.05 to 10% by weight with the remainderbeing the injectable carrier and the like.

The above described components for orally administered or injectablecompositions are merely representative. Further materials as well asprocessing techniques and the like are set out in Part 5 of Remington'sPharmaceutical Sciences, 20^(th) Edition, 2000, Marck PublishingCompany, Easton, Pa., which is incorporated herein be reference.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can also befound in the incorporated materials in Remington's PharmaceuticalSciences.

In the following the present invention shall be illustrated by means ofsome examples which are not construed to be viewed as limiting the scopeof the invention. The following abbreviations are hereinafter used inthe accompanying examples: min (minute), h (hour), g (gram), mg(milligram), mmol (millimole), m.p. (melting point), eq (equivalents),mL (milliliter), μL (microliters), mL (milliliters), ACN (Acetonitrile),DBU (Diazabicyclo [5.4.0]undec-7-ene), DIEA (Diisopropylethylamine),CDCl₃ (deuterated chloroform), cHex (Cyclohexanes), DCM(Dichloromethane), DIC (Diisopropyl carbodiimide), DMAP(4-Dimethylaminopyridine), Pd(PPh₃)₄ (Tetrakis triphenylphosphinepalladium), DMF (Dimethylformamide), DMSO (Dimethylsulfoxide), DMSO-d₆(deuterated dimethylsulfoxide), EDC(1-(3-Dimethyl-amino-propyl)-3-ethylcarbodiimide), EtOAc (ethylacetate), Et₂O (Diethyl ether), EtOH (Ethanol), HOBt(1-Hydroxybenzotriazole), K₂CO₃ (potassium carbonate), NaH (Sodiumhydride), NaHCO₃ (Sodium bicarbonate), nBuLi (n-Butyl-lithium), TEA(Triethylamine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran),MgSO₄ (Magnesium sulfate), PetEther (Petroleum ether), rt (roomtemperature).

EXAMPLES Example 1N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamidea) Preparation of methyl 4-[(3-phenylpropanoyl)amino]benzoate (CompoundC of Scheme 2)

To a solution of methyl 4-aminobenzoate (825 mg, 5.46 mmol) in anhydrouspyridine (16 mL) was added dropwise hydrocinnamoyl chloride (990 μL) at0° C. After 5 min, the temperature was allowed to warm up to rt. After90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g,1200 mg) was added and the resulting mixture was stirred overnight atrt. After rinsing the resin and filtration, water (200 mL) was added tothe filtrate and a white solid precipated out. Filtration and washingwith water gave a solid which was dried under vacuo at 60° C. overnight.The title compound (1.40 g) was obtained as a white solid (90%) in 98.2%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H), 7.89 (d, J=8.9 Hz, 2H), 7.71(d, J=8.9 Hz, 2H), 7.26 (m, 4H), 7.17 (m, 1H), 3.80 (s, 3H), 2.91 (t,J=7.6 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H) M⁻(APCI⁻): 282.

b) Preparation of N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide(Scheme 2, compound B)

To a suspension of methyl 4-[(3-phenylpropanoyl)amino]benzoate (1.40 g,4.94 mmol) in EtOH (16 mL) was added hydrazine hydrate (3.6 mL). Afterstirring for 16 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with water (4×5 mL)and drying under vacuo at 60° C. for 2 hrs gave 1.08 g of the titlecompound (77%) as a white solid in 99.1% puity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.06 (s, 1H), 9.56 (s, 1H), 7.71 (d, J=8.7Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.21 (m, 4H), 7.12 (m, 1H), 4.37 (s,2H), 2.85 (t, J=7.7 Hz, 2H), 2.59 (t, J=7.7 Hz, 2H).

c) Preparation ofN-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide (compound B). Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 360 mg of the titlecompound (77%) as a yellow powder in 99.4% purity by HPLC (R_(t): 4.68,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 297° C.

IR(neat) v 3165, 1661, 1521, 1500, 1269, 1141, 1122, 921 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.32 (s, 1H),7.82 (m, 5H), 7.71 (dd, J=8.3, 1.7 Hz, 1H), 7.27 (m, 4H), 7.17 (m, 1H),6.81 (d, J=8.3 Hz, 2.92 (t, J=7.5 Hz,2H),2.68 (t, J=7.5 Hz, 2H).

M⁻(ESI⁻): 537, M⁺(ESI⁺): 539.

Analysis calculated for C₂₄H₁₉IN₄O₃.0.8 H₂O: C, 52.15; H, 3.76; N,10.14%. Found: C, 52.12; H, 3.74; N, 10.08%.

Example 2 3,5-Dichloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3,5-dichlorobenzohydrazide. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 159 mg of the title compound (69%) as a orange solid in90% purity by HPLC (R_(t): 5.86, 6.66, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 337° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.69 (s, 0.4H), 11.89 (s, 0.6H), 11.48 (s,0.4H); 10.93 (s, 0.6H), 8.33 (br, 0.6H), 7.97 (br s, 0.4H), 7.93-7.80(m, 3H), 7.72 (br d, J=8.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 0.4H), 6.75 (d,J=8.3 Hz, 0.6H).

M⁻(APCI⁻): 460.

Example 3 N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added benzohydrazide.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 129 mg ofthe title compound (66%) as a yellow solid in 99.8% purity by HPLC(R_(t): 4.72, gradient of 10 min, MaxPlot detection between 230 and 400nm).

M.p. 318° C.

IR (neat) v 3248, 1699, 1673, 1599, 1515, 1458, 1139, 913 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.83 (s, 1H), 11.46 (s, 1H), 7.89 (m, 2H),7.82 (br s, 1H), 7.69 (m, 2H), 7.61 (m, 2H), 6.81 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 390; M⁺(APCI⁺): 392.

Analysis calculated for C₁₅H₁₀IN₃O₂.0.3 H₂O: C, 45.43; H, 2.69; N,10.60%. Found: C, 45.21; H, 2.57; N, 10.51%.

Example 4N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methylbenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-methylbenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 163 mg of the title compound (80%) as a yellow solid in99.99% purity by HPLC (R_(t): 5.7, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 332° C. (decomp).

IR (neat) v 3218, 1674, 1611, 1459, 1268, 1134, 118, 916 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.45 (s, 1H), 7.80 (m, 3H),7.71 (dd, J=8.1, 1.7 Hz, 1H), 7.42 (d, J=7.9 Hz, 2H), 6.81 (d, J=8.3 Hz,1H), 2.40 (s, 3H).

M⁻(APCI⁻): 404; M⁺(APCI⁺): 406.

Analysis calculated for C₁₆H₁₂IN₃O₂.0.2 H₂O: C, 47.01; H, 3.06; N,10.28%. Found: C, 47.03; H, 2.98; N, 10.26%.

Example 54-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 174 mg of the title compound (85%) as a yellow solid in99.8% purity by HPLC (R_(t): 4.7, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 328° C. (decomp).

IR (neat) v 3139, 1655, 1601, 1538, 1505, 1141, 1114, 916 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.77 (s, 1H), 11.43 (s, 1H), 10.42 (s, 1H),7.81 (d, J=1.5 Hz, 1H), 7.76 (d, J=8.7 Hz, 2H), 7.69 (dd, J=8.3, 1.5 Hz,1H), 6.94 (d, 8.7 Hz, 2H), 6.80 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 406; M⁺(APCI⁺): 408.

Analysis calculated for C₁₅H₁₀IN₃O₃: C, 44.25; H, 2.48; N, 10.32%.Found: C, 44.12; H, 2.52; N, 10.24%.

Example 63-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 133 mg of the title compound (65%) as a yellow solid in99.4% purity by HPLC (R_(t): 4.83, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 343° C. (decomp).

IR (neat) v 3269, 3149, 3047, 1665, 1579, 1521, 1481, 1290, 1141, 849,806 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.78 (s, 1H), 11.45 (s, 1H), 9.99 (s, 1H),7.82 (br s, 1H), 7.71 (dd, J=8.1, 1.5 Hz, 1H), 7.40 (m, 1H), 7.29 (m,2H), 7.06 (m, 1H), 6.81 (d, J=8.1 Hz, 1H).

M⁻(APCI⁻): 406; M⁺(APCI⁺): 408.

Analysis calculated for C₁₅H₁₀IN₃O₃.0.2 H₂O: C, 43.86; H, 2.55; N,10.23%. Found: C, 43.81; H, 2.48; N, 10.09%.

Example 72-nitro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3dione in acetic acid was added2-nitrobenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 159 mg of the title compound (73%) as a yellow solid in99.2% purity by HPLC (R_(t): 5.67, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 321° C. (decomp).

IR (neat) v 3166, 1679, 1519, 142, 1344, 1319 1151, 1127, 791 cm⁻¹.

M⁻(APCI⁻): 435; M⁺(APCI⁺): 437.

Analysis calculated for C₁₅H₉IN₄O₄.0.3 H₂O: C, 40.80; H, 2.19; N,12.69%. Found: C, 40.80; H, 2.21; N, 12.63%.

Example 8N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-phenoxybenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3dione in acetic acid was added4-phenoxybenzohydrazide. After stirring at 100 ° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 4940 mg of the title compound (93%) as a yellow solid in99.9% purity by HPLC (R_(t): 5.13, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 296° C.

IR (neat) v 3252, 1671, 1607, 1580, 1482, 1455, 1230, 1139, 756 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.80 (s, 1H), 11.47 (s, 1H), 7.91 (m, 2H),7.82 (d, J=1.5 Hz, 1H), 7.70 (dd, J=8.3, 1.5 Hz, 1H), 7.45 (m, 2H), 7.25(m, 1H), 7.15 (m, 4H), 6.80 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 482; M⁺(APCI⁺): 484.

Analysis calculated for C₂₁H14IN₃O₃.0.2 H₂O: C, 51.81; H, 2.98; N,8.63%. Found: C, 51.77, H, 3.15; N, 8.65%.

Example 9N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-trifluoromethyl)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3one in acetic acid was added4-(trifluoromethyl)benzohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 151 mg of the title compound (66%) as a yellowsolid in 99.9% purity by HPLC (R_(t): 6.3, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 306° C. (decomp).

IR (neat) v 3238, 1703, 1674, 1460, 1326, 1108, 913 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.83 (s, 1H), 11.48 (s, 1H), 8.08 (d, J=8.3Hz, 2H), 7.99 (d, J=8.3 Hz, 2H), 7.82 (br s, 1H), 7.72 (br d, J=8.1 Hz,1H), 6.80 (d, J=8.1 Hz, 1H).

M⁻(APCI⁻): 458; M⁺(APCI⁺): 460.

Analysis calculated for C₁₆H₉F₃IN₃O₂.0.5 H₂O: C, 41.05; H, 2.15; N,8.98%. Found: C, 40.95; H, 2.02; N, 8.94%.

Example 10 4-tert-Butyl-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-tert-butylbenzohydrazide. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 168 mg of the title compound (75%) as a yellow solid in99.8% purity by HPLC (R_(t): 6.65, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 326° C. (decomp).

IR (neat) v 3216, 2961, 1704, 1668, 1609, 1458, 1269, 1207, 1123, 916cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.46 (s, 1H), 7.83 (m, 3H),7.70 (dd, J=8.1, 1.7 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 6.80 (d, J=8.1 Hz,1H), 1.32 (s, 9H).

M⁻(APCI⁻): 446; M⁺(APCI⁺): 448.

Analysis calculated for C₁₉H₁₈IN₃O₂.0.3 H₂O: C, 5.41; H, 4.14; N, 9.28%.Found: C, 5.28; H, 3.95; N, 9.25%.

Example 11N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)[1,1′-biphenyl]-4-carbohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added(1,1′-biphenyl)-4-carbohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 201 mg of the title compound (86%) as a yellowsolid in 99.8% purity by HPLC (R_(t): 6.49, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 337° C. (decomp).

IR (neat) v 3247, 1698, 1671, 1606, 1468,;1260, 1120, 915, 736 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.89 (s, 1H), 11.47 (s, 1H), 7.98 (d, J=8.4Hz, 2H), 7.91 (d, J=8.4 Hz, 2H), 7.83 (br s, 1H), 7.77 (d, J=7.2 Hz,2H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 7.52 (m, 2H), 7.44 (m, 1H), 6.81 (d,J=8.3 Hz, 1H).

M⁻(APCI⁻): 466; M⁺(APCI⁺): 468.

Analysis calculated for C₂₁H₁₄IN₃O₂: C,53.98; H,3.02; N,8.99%. Found: C,53.72; H, 2.99; N, 8.92%.

Example 124-Bromo-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-bromobenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 193 mg of the title compound (82%) as a yellow solid in99.6% purity by HPLC (R_(t): 6.03, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 337° C. (decomp).

¹H NMR (DMSO-d₄, 300 MHz) δ 13.79 (s, 1H), 11.47 (s, 1H), 7.83 (m, 5H),7.71 (dd, J=8.3, 1.7 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 470; M⁺(APCI⁺): 472.

Example 13N′-(5-Iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)-3-nitrobenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3-nitrobenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 176 mg of the title compound (81%) as a orange solid in98.4% purity by HPLC (R_(t): 5.61, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 324° C. (decomp).

IR (neat) v 3162, 3078, 1682, 1526, 1354, 1155, 828 cm⁻¹.

M⁻(APCI⁻): 435.

Analysis calculated for C₁₅H₉IN₄O₄: C,41.31; H,2.08; N,12.85%. Found: C,41.21; H, 2.16; N, 12.67%.

Example 14N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methoxybenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave,347 mg of the title compound (82%) as a yellow solid in99.9% purity by HPLC (R_(t): 5.44, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 300° C. (decomp).

IR (neat) v 3208, 1695, 1661, 1461, 1246, 1178, 1113, 1027, 914, 847,815 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.80 (s, 1H), 11.45 (s, 1H), 7.86 (d, J=8.9Hz, 2H), 7.82 (d, J=1.7 Hz, 1H), 7.70 (dd, J=8.1, 1.7 Hz, 1H), 7.14 (d,J=8.9 Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 3.85 (s, 3H).

M⁻(APCI⁻): 420; M⁺(APCI⁺): 422.

Analysis calculated for C₁₆H₁₂IN₃O₃: C, 45.63; H, 2.87; N, 9.98%. Found:C, 45.49; H, 2.86; N, 9.92%.

Example 15N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-methoxybenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3-methoxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 345 mg of the title compound (82%) as a yellow solid in99.7% purity by HPLC (R_(t): 5.5, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 287° C.

IR (neat) v 3137, 1677, 1588, 1517, 1441, 1204, 1130, 837, 745 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.45 (s, 1H), 7.83 (br s,1H), 7.71 (dd, J=8.1, 1.7 Hz, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 7.26 (m,1H), 6.81 (d, J=8.1 Hz, 1H), 3.84 (s, 3H).

M⁻(APCI⁻): 420; M⁺(APCI⁺): 422.

Analysis calculated for C₁₆H₁₂IN₃O₃.0.2 H₂O: C,45.24; H,2.94; N,9.89%.Found: C, 45.19; H, 2.85; N, 9.86%.

Example 164-Amino-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-aminobenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 395 mg of the title compound (97%) as a yellow solid in99.2% purity by HPLC (R_(t): 4.41, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 299° C. (decomp).

IR (neat) v 3452, 3350, 3091. 1695, 1598, 1495, 1149, 756 cm⁻¹.

¹H NMR (DMSO-₆, 300 MHz) δ 13.74 (s, 1H), 11.40 (s, 1H), 7.80 (d, J=1.7Hz, 1H), 7.68 (dd, J=8.1, 1.7 Hz, 1H), 7.60 (d, J=8.7 Hz, 2H), 6.80 (d,J=8.1 Hz, 1H), 6.65 (d, J=8.7 Hz, 2H), 6.10 (s, 2H).

M⁻(APCI⁻): 405; M⁺(APCI⁺): 407.

Analysis calculated for C₁₅H₁₁IN₄O₂.H₂O: C,43.80; H,3.24; N,12.02%.Found: C, 43.67; H, 3.24; N, 11.95%.

Example 174-(Dimethylamino)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(dimethylamino)benzohydrazide. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out.

Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 346 mg of the title compound (80%) as a orangesolid in 99.5% purity by HPLC (R_(t): 5.38, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 324° C.

IR (neat) v 3186, 1661, 1601, 1506, 1441, 1267, 1120, 755 cm⁻¹.

¹H NMR (DMSO-₆, 300 MHz) δ 13.80 (s, 1H), 11.41 (s, 1H), 7.81 (br s,1H), 7.73 (d, J=9.0 Hz, 2H), 7.68 (br d, J=7.9 Hz, 1H), 6.82 (d, J=9.0Hz, 2H), 6.80 (d, J=7.9 Hz, 1H), 3.02 (s, 6H).

M⁻(APCI⁻): 433.

Analysis calculated for C₁₇H₁₅IN₄O₂: C,47.02; H,3.48; N,12.90%. Found:C, 46.74; H, 3.46; N, 12.73%.

Example 18 N′-(5-Iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)-2-(4-nitrophenoxy)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-(4-nitrophenoxy)acetohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 395 mg of the title compound (85%) as a yellowsolid in 97.3% purity by HPLC (R_(t): 5.76, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 308° C. (decomp).

IR (neat) v 3172, 3071, 1693, 1594, 1491, 1340, 1264, 1118, 838 cm⁻¹.

¹H NMR (DMSO-₆, 300 MHz) δ 13.59 (br s, 0.5H), 12.49 (br s, 0.5H), 11.37(s, 1H), 8.24 (m, 2H), 7.85 (m, 1H), 7.71 (dd, J=8.3, 1.9 Hz, 1H), 7.24(m, 2H), 6.80 (d, J=8.3 Hz, 1H), 5.49 (br s, 1H), 5.09 (br s, 1H).

M⁻(APCI⁻): 465.

Analysis calculated for C₁₆H₁₁IN₄O₅: C,41.22; H,2.38; N,12.02%. Found:C, 41.04; H, 2.41; N, 11.85%.

Example 19N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(trifluoromethoxy)-benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3dione in acetic acid was added4-(trifluoromethoxy)benzohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 135 mg of the title compound (57%) as a yellowsolid in 99.7% purity by HPLC (R_(t): 6.39, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 306° C.

IR (neat) v 3285, 1707, 1672, 1605, 1496, 1461, 1248, 1599, 1141, 914cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.79 (s, 1H), 11.47 (s, 1H), 8.01 (d, J=8.5Hz, 2H), 7.81 (br s, 1H), 7.71 (dd, J=8.3, 1.9 Hz, 1H), 7.61 (d, J=8.5Hz, 2H), 6.80 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 474.

Analysis calculated for C₁₆H₉F₃IN₃O₃: C,40.44; H,1.91; N,8.84%. Found:C, 40.39; H, 2.12; N, 8.80%.

Example 20

N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,1,3-benzoxadiazole-5-carbohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2,1,3-benzoxadiazole-5-carbohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 166 mg of the title compound (77%) as a orangesolid in 99.1% purity by HPLC (R_(t): 5.65, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 348° C. (decomp).

IR (neat) v 3212, 1698, 1681, 1613, 1520, 1459, 1237, 1130, 881, 748cm⁻¹.

M⁻(APCI⁻): 432.

Analysis calculated for C₁₅H₈IN₅O₃.0.35 H₂O: C,41.00; H,2.00; N,15.94%.Found: C, 41.00; H, 2.01; N, 15.80%.

Example 21N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-((5-nitro)-2-furohydrazide)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added5-nitro-2-furohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 158 mg of the title compound (74%) as a Orange solid in98.3% purity by HPLC (R_(t): 5.31, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 351° C. (decomp).

IR (neat) v3131, 1678, 1538, 1256, 1145, 1026, 820cm⁻¹.

¹H NMR (DMSO-₆, 300 MHz) δ 13.86 (br s, 1H), 11.46 (s, 1H), 7.88 (br s,1H), 7.84 (d, J=3.8 Hz, 7.73 (m, 2H), 6.81 (d, J=7.9 Hz, 1H).

M⁻(APCI⁻): 425.

Analysis calculated for C₁₃H₇IN₄O₅: C,36.64; H,1.66; N,13.15%. Found: C,36.52; H, 1.87; N, 12.88%.

Example 22 Methyl4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl4-(hydrazinocarbonyl)benzoate. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 334 mg of the title compound (86%) as a yellow solid in98.3% purity by HPLC (R_(t): 5.21, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 342° C. (decomp).

IR (neat) v 3222, 1674, 1531, 1436, 1286, 1112, 917, 810 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 11.47 (s, 1H), 8.16 (d, J=8.1Hz, 2H), 8.01 (d, J=8.1 Hz, 2H), 7.82 (s, 1H), 7.72 (d, J=8.3 Hz, 1H),6.81 (d, J=8.3 Hz, 1H), 3.90 (s, 3H).

M⁻(APCI⁻): 448.

Analysis calculated for C₁₇H₁₂IN₃O₄.0.5 H₂O: C,44.56; H,2.86; N,9.17%.Found: C, 44.47; H, 2.81; N, 9.16%.

Example 23 Methyl4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 185 mg of the title compound (77%) as a yellowsolid in 99.1% purity by HPLC (R_(t): 5.34, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p.288° C.

IR (neat) v 3307, 3208, 1698, 1605, 1503, 1428, 1168, 1114, 763 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.61 (br s, 0.5H), 12.49 (br s, 0.5H),11.35 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.83 (m, 1H), 7.70 (dd, J=8.1,1.9 Hz, 1H), 7.13 (d, J=8.5 Hz, 2H), 6.79 (d, J=8.1 Hz, 1H), 5.40 (br s,1H), 4.99 (br s, 1H), 3.81 (s, 3H).

M⁻(APCI⁻): 478.

Analysis calculated for C₁₈H₁₄IN₃O₅.0.4 H₂O: C,44.45; H,3.07; N,8.64%.Found: C, 44.46; H, 2.96; N, 8.68%.

Example 244-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzoicacid

Into a suspension of methyl4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoate(80 mg, 0.18 mmol) in THF (5 mL) was added NaOH (0.2 M, 2.5 mL). Theresulting solution was stirred at rt for 5 hrs and quenched with HCl(1N, 2 mL) and water (5 mL). A yellow solid precipitated out.Filtration, washing with water (2×1 mL) and drying under vacuo at rt for72 hrs to give the tilte compound as a yellow powder (58 mg, 75%) in98.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 370° C. (decomp).

¹H NMR (300 MHz, DMSO-d₆) δ 13.85 (s, 1H), 13.30 (s, 1H), 11.48 (s, 1H),8.13 (d, J=7.9 Hz, 2H), 7.99 (d, J=7.9 Hz, 2H), 7.83 (s, 1H), 7.72 ((d,J=7.9 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H).

M⁻(APCI⁻): 434. M⁺(APCI⁺): 436.

Example 254-Iodo-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-iodobenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 430 mg of the title compound (83%) as a yellow solid in98.7% purity by HPLC (R_(t): 6.19, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 326° C.

IR (neat) v 3263, 1704, 1673, 1471, 1455, 1264, 1524, 884, 741 cm⁻¹.

¹H NMR (DMSO-₆, 300 MHz) δ 13.79 (s, 1H), 11.47 (s, 1H), 8.01 (d, J=8.5Hz, 2H), 7.82 (br s, 1H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 6.80 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 516; M⁺(APCI⁺): 518.

Analysis calculated for C₁₅H₉I₂N₃O₂: C,34.84; H,1.75; N,8.13%. Found: C,34.88; H, 1.73; N, 8.18%.

Example 26N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-phenoxybenzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3-phenoxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 403 mg of the title compound (83%) as a yellow solid in99.5% purity by HPLC (R_(t): 6.58, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 283° C.

IR (neat) v 3163, 1688, 1585, 1513, 1444, 1244, 1135, 1006, 738 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.79(s, 1H), 11.46 (s, 1H), 7.81 (br s,1H), 7.71 (dd, J=8.1, 1.7 Hz, 1H), 7.64 (m, 2H), 7.45 (m, 3H), 7.32 (m,1H), 7.21 (t, J=7.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 2H), 6.80 (d, J=8.1 Hz,1H).

M⁻(APCI⁻): 482, M⁺(APCI⁺): 484.

Analysis calculated for C₂₁H₁₄IN₃O₃: C,52.19; H,2.92; N,8.69%. Found: C,52.22; H, 2.97; N, 8.62%.

Example 27N′-(5-Iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)-2-(4-iodophenoxy)-acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-(4-iodophenoxy)acetohydrazide. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 173 mg of the title compound (79%) as a yellow solid in96.4% purity by HPLC (R_(t): 6.41, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 275° C.

M⁻(APCI⁻): 546; M⁺(APCI⁺): 548.

Example 28N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[(4-methylphenyl)sulfonyl]acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[(4-methylphenyl)sulfonyl]acetohydrazide. After stirring at 100° C.,the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 199 mg of the title compound (82%) as ayellow solid in 91.1% purity by HPLC (R_(t): 5.38, gradient of 10 min,MaxPlot detection between 230 and 400 nm).

M.p. 257° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 12.98 (s, 0.33H), 12.41 (s, 0.67H), 11.32(s, 1H), 7.78 (d, J=7.9 Hz, 2H), 7.69 (m, 2H), 7.45 (d, J=7.9 Hz,0.67H), 7.30 (d, J=7.9 Hz, 1.33H), 6.76 (m, 1H), 4.96 (s, 1.33H), 4.83(s, 0.67H), 2.40 (s, 1H), 2.17 (s, 2H).

M⁻(APCI⁻): 482; M⁺(APCI⁺): 484.

Example 292-{[(2-Furylmethyl)sulfonyl]methyl}-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4-carbohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-{[(2-furylmethyl)sulfonyl]methyl}-1,3-thiazole-4-carbohydrazide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 32 mg of the titlecompound (63%) as a yellow solid in 99.3% purity by HPLC (R_(t): 4.8,gradient of 10 min, MaxPlot detection between 230 and 400 nm).

M.p. 306° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 14.24 (s, 1H), 11.39 (s, 1H), 8.73 (s, 1H),7.84 (br s, 1H), 7.74 (br s, 1H), 7.70 (dd, J=8.1, 1.5 Hz, 1H), 6.76 (d,J=8.1 Hz, 1H), 6.67 (d, J=3.0 Hz, 6.51 (m, 1H), 5.17 (s, 2H), 4.94 (s,2H).

M⁻(APCI⁻): 555; M⁺(APCI⁺): 557.

Example 302-Hydroxy-N′-(-5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 344 mg of the title compound (84%) as a yellow solid in98.5% purity by HPLC (R_(t): 4.61, gradient of 10 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 327° C. (decomp).

IR (neat) v 3298, 1704, 1646, 1610, 1530, 1444, 1294, 1202, 1121, 914,743 cm⁻¹.

⁻H NMR (DMSO-d₆, 300 MHz) δ 14.33 (s, 1H), 11.71 (s, 1H), 11.24 (s, 1H),7.99,(d, J=7.2 Hz, 1H), 7.79 (br s, 1H), 7.68 (dd, J=8.1, 1.5 Hz, 1H),7.45 (m, 1H), 6.99 (m, 2H), 6.77 (d, J=8.1 Hz, 1H).

M⁻(APCI⁻): 406.

Analysis calculated for C₁₅H₁₀IN₃O₃: C,44.25; H,2.48; N,10.32%. Found:C, 44.21; H, 2.66; N, 10.27%.

Example 31N-(2-Furylmethyl)-N′-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}urea

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-(2-furylmethyl)-N′-(2-hydrazino-2-oxoethyl)urea. After stirring at100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 71 mg of the title compound(71%) as a yellow solid in 95.6% purity by HPLC (R_(t): 4.26, gradientof 10 min, MaxPlot detection between 230 and 400 nm).

M.p. 257° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.20 (br s, 0.5H), 12.42 (br s, 0.5H),11.33 (s, 1H), 7.81 (s, 1H), 7.69 (d, J=7.9 Hz, 1H), 7.55 (s, 1H), 6.78(d, J=7.9 Hz, 1H), 6.71 (br s, 1H), 6.53 (br s, 1H), 6.36 (s, 1H), 6.22(s, 1H), 4.32 (br s, 1H), 4.21 (s, 2H), 3.89 (br s, 1H).

M⁻(APCI⁻): 466; M⁺(APCI⁺): 468.

Example 32N′-(5-Iodo-2oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(methylsulfanyl)-benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(methylsulfanyl)benzohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 411 mg of the title compound (94%) as a yellowsolid in 99.3% purity by HPLC (R_(t): 5.75, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 298° C.

M⁻(APCI⁻): 436; M⁺(APCI⁺): 438.

Example 33 Methyl6-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}nicotinate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl6-(hydrazinocarbonyl)nicotinate. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 33 mg of the title compound (73%) as a yellow solid in89.7% purity by HPLC (R_(t): 4.44, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 349° C. (decomp).

M⁻(APCI⁻): 449; M⁺(APCI⁺): 451.

Example 34 Benzyl4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoatea) Preparation of benzyl 4-(2-hydrazino-2-oxoethoxy)benzoate (Scheme 2,compound B)

To a suspension of benzyl 4-(2-methoxy-2-oxoethoxy)benzoate (1.0 g, 3.33mmol) in MeOH (15 mL) was added hydrazine hydrate (1.7 mL). Afterstirring for 1 h at rt, the reaction mixture was filtered. The cake waswashed with MeOH (3×4 mL) and dryed under vacuo at 50° C. overnight gave936 mg of the title compound (94%) as a white solid in 99.7% purity byHPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 9.40 (s, 1H), 7.94 (d, J=8.8 Hz, 2H),7.46-7.31 (m, 5H), 7.06 (d, J=8.8 Hz, 2H), 5.31 (s, 2H), 4.57 (s, 2H),4.34 (s, 2H).

b) Preparation of benzyl4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]-2-oxoethoxy}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added benzyl4-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 215 mg of the title compound (77%) as a orangepowder in 98.3% purity by HPLC (R_(t): 5.16, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 221° C.

IR (neat) v 3223, 1698, 1606, 1506, 1288, 1243, 1167, 1127, 765 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.62 (s, 0.6H), 12.47 (s, 0.4H), 11.36 (s,1H), 7.97 (d, J=8.3 Hz, 2H), 7.82 (br s, 1H), 7.70 (dd, J=8.3, 1.9 Hz,1H), 7.47-7.41 (m, 5H), 7.14 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.3 Hz, 1H),5.41 (br s, 0.8H), 5.32 (s, 2H), 4.98 (br s, 1.2H).

M⁻(ESI⁻): 554; M⁺(ESI⁺): 556.

Example 35N-4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-2-furamidea) Preparation of N-[4-hydrazinocarbonyl)phenyl]-2-furamide (Scheme 2,compound B)

To a suspension of methyl 4-(2-furoylamino)benzoate (483 mg, 1.97 mmol)in EtOH (6 mL) was added hydrazine hydrate (1.5 mL). After stirring for15 h at reflux, the reaction mixture was cooled to rt and a white solidprecipitated out. Filtration, washing with EtOH (2 mL) and water (2×2mL), and drying under vacuo at rt for 72 hrs gave 242 mg of the titlecompound (50%) as a white solid in 99.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.36 (s, 1H), 9.65 (s, 1H), 7.95 (br s,1H), 7.80 (s, 4H), 7.36 (d, J=3.4 Hz, 1H), 6.71 (dd, J=3.4, 1.5 Hz, 1H),4.43 (s, 2H).

b) Preparation ofN-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-2-furamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]-2-furamide. After stirring at 100° C.the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 81 mg of the title compound (81%) as ayellow powder in 96.7% purity by HPLC (R_(t): 4.05, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 343° C. (decomp.).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.83 (s, 1H), 11.46 (s, 1H), 10.55 (s, 1H),8.00 (m, 3H), 7.89 (d, J=9.0 Hz, 2H), 7.83 (d, J=1.7 Hz, 1H), 7.71 (dd,J=8.1, 1.7 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.73(dd, J=3.4, 1.8 Hz, 1H).

M⁻(APCI⁻): 499; M⁺(APCI⁺): 501.

Example 36N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)hexanamidea) Preparation of methyl 4-(hexanoylamino)benzoate (Compound C of Scheme2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrouspyridine (10 mL) was added dropwise hexanoyl chloride (550 μl) at 0° C.After 5 min the temperature was allowed to warm up to rt. After 90 minaminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg)was added and the resulting mixture was stirred overnight at rt. Afterfiltration and rinsing the resin, water (125 mL) was added to thefiltrate and a white solid precipated out. Filtration and washing withwater gave a solid which was dried under vacuo at 60° C. overnight. Thetitle compound (699 mg) was obtained as a white solid (85%) in 96.9%purity by HPLC (MaxPlot detection between 230 and 400 mn).

¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.72(d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.32 (t, J=7.4 Hz, 2H), 1.58 (m, 2H),1.28 (m, 4H), 0.86 (t, J=6.8 Hz, 3H).

M⁻(APCI⁻): 248.

b) Preparation of N-[4-(hydrazinocarbonyl)phenyl]hexanamide (Scheme 2,compound B)

To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol)in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for15 h at reflux, the reaction mixture was cooled to rt and a white solidprecipitated out. Filtration, washing with water (2×2 mL), and dryingunder vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) asa white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.06 (s, 1H), 9.60 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 4.42 (s, 2H), 2.30 (t, J=7.2 Hz, 2H),1.58 (m, 2H), 1.28 (m, 4H), 0.86 (m, 3H).

c) Preparation ofN-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)hexanamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]hexanamide. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 87 mg of the title compound (86%) as a yellowpowder in 98.5% purity by HPLC (R_(t): 4.71, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 305° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.27 (s, 1H),7.82 (m, 5H), 7.71 (d, J=8.3 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 2.34 (t,J=7.4 Hz, 2H), 1.60 (m, 2H), 1.29 (m, 4H), 0.87 (t, J=6.6 Hz, 3H).

M⁻(APCI⁻): 503; M⁺(APCI⁺): 505.

Example 374-Cyano-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)benzamidea) Preparation of ethyl 4-[(4-cyanobenzoyl)amino]benzoate (Compound C ofScheme 2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrouspyridine (10 mL) was added dropwise 4-cyanobenzoyl chloride (660 mg) at0° C. After 5 min the temperature was allowed to warm up to rt. After 90min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720mg) was added and the resulting mixture was stirred overnight at rt.After filtration and rinsing the resin, water (125 mL) was added to thefiltrate and a white solid precipated out. Filtration and washing withwater gave a solid which was dried under vacuo at 60° C. overnight. Thetitle compound (854 mg) was obtained as a pale yellow solid (92%) in95.2% purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.78 (s, 1H), 8.11 (d, J=8.3 Hz, 2H), 8.03(d, J=8.3 Hz, 2H), 7.97 (d, J=8.8 Hz, 2H), 7.93 (d, J=8.8 Hz, 2H), 3.83(s, 3H).

M⁻(APCI⁻): 279.

b) Preparation of 4-cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide(Scheme 2, compound B)

To a suspension of methyl 4-[(4-cyanobenzoyl)amino]benzoate (680 mg,2.43 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.8 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (1×2 mL) andwater (2×2 mL), and drying under vacuo at rt for 72 hrs gave 432 mg ofthe title compound (64%) as a pale yellow solid in 94.2% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.65 (s, 1H), 9.68 (s, 1H), 8.10 (d, J=8.3Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.83 (s, 4H), 4.46 (s, 2H).

c) Preparation of4-Cyano-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}phenyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-cyano-N-[4-(hydrazinocarbonyl)phenyl]benzamide. After stirring at 100°C. the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 95 mg of the title compound (89%) as aorange powder in 94.7% purity by HPLC (R_(t): 4.37, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 349° C. (decomp.).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 11.46 (s, 1H), 10.84 (s, 1H),8.13 (d J=8.5 Hz, 2H), 8.05 (d, J=8.5 Hz, 2H), 8.01 (d, J=8.6 Hz, 2H),7.92 (d, J=8.6 Hz, 2H), 7.84 (d, J=1.5 Hz, 1H), 7.72 (dd, J=8.3, 1.5 Hz,1H), 6.82 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 534.

Example 384-(Hexloxy)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamidea) Preparation of methyl 4-{[4-(hexyloxy)benzoyl]amino}benzoate(Compound C of Scheme 2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrouspyridine (10 mL) was added dropwise 4-(hexyloxy)benzoyl chloride (890μL) at 0° C. After 5 min the temperature was allowed to warm up to rt.After 90 min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93mmol/g, 720 mg) was added and the resulting mixture was stirredovernight at rt. After filtration and rinsing the resin, water (125 mL)was added to the filtrate and a white solid precipated out. Filtrationand washing with water gave a solid which was dried under vacuo at 60°C. overnight. The title compound (1073 mg) was obtained as a white solid(91%) in 99.7% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.94 (m, 6H), 7.05 (d, J=9.1Hz, 2H), 4.04 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 1.72 (m, 2H), 1.41 (m,2H), 1.30 (m, 4H), 0.87 (t, J=6.8 Hz, 3H).

M^(− (APCI) ⁻): 354. M⁺(APCI⁺): 356.

b) Preparation of 4-(hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]benzamide(Scheme 2, compound B)

To a suspension of methyl 4-{[4-(hexyloxy)benzoyl]amino}benzoate (856mg, 2.41 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL).After stirring for 15 h at reflux, the reaction mixture was cooled to rtand a white solid precipitated out. Filtration, washing with EtOH (1×2mL) and water (2×2 mL), and drying under vacuo at rt for 72 hrs gave 681mg of the title compound (80%) as a white solid in 99.7% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.25 (s, 1H), 9.64 (s, 1H), 7.94 (d, J=8.9Hz, 2H), 7.83 (d, J=9.0 Hz, 2H), 7.80 (d, J=9.0 Hz, 2H), 7.05 (d, J=8.9Hz, 2H), 4.43 (s, 2H), 4.04 (t, J=6.4 Hz, 2H), 1.73 (m, 2H), 1.42 (m,2H), 1.30 (m, 4H), 0.87 (t, J=6.8 Hz, 3H).

c) Preparation of4-(Hexyloxy)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(hexyloxy)-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirringat 100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 110 mg of the title compound(90%) as a yellow powder in 91.1% purity by HPLC (R_(t): 5.86, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 313° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 11.46 (s, 1H), 10.44 (s, 1H),7.99.(m, 4H), 7.89 (d, J=7.5 Hz, 2H), 7.84 (s, 1H), 7.72 (d, J=7.9 Hz,1H), 7.07 (d, J=7.6 Hz, 2H), 6.82 (d, J=7.9 Hz, 1H), 4.05 (m, 2H), 1.73(m, 2H), 1.42 (m, 2H), 1.31 (m, 4H), 0.88 (m, 3H).

M⁻(APCI⁻): 609; M⁺(APCI⁺): 611.

Example 394-Heptyl-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamidea) Preparation of methyl 4-[(4-heptylbenzoyl)amino]benzoate (Scheme 2,compound C)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrouspyridine (10 mL) was added dropwise 4-heptylbenzoyl chloride (950 μL) at0° C. After 5 min the temperature was allowed to warm up to rt. After 90min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720mg) was added and the resulting mixture was stirred overnight at rt.After filtration and rinsing the resin, water (125 mL) was added to thefiltrate and a white solid precipated out. Filtration and washing withwater gave a solid which was dried under vacuo at 60° C. overnight. Thetitle compound (1051 mg) was obtained as a white solid (90%) in 96.9%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.47 (s, 1H), 7.94 (s, 4H), 7.88 (d, J=8.1Hz, 2H), 7.35 (d, J=8.1 Hz, 2H), 3.82 (s, 3H), 2.64 (t, J=7.6 Hz, 2H),1.58 (m, 2H), 1.26 (m, 8H), 0.84 (t, J=6.5 Hz, 3H).

M⁻(APCI⁻): 352. M⁺(APCI⁺): 354.

b) Preparation of 4-heptyl-N-[4-(hydrazinocarbonyl)phenyl]benzamide(Scheme 2, compound B)

To a suspension of methyl 4-[(4-heptylbenzoyl)amino]benzoate (823 mg,2.33 mmol) in EtOH (10 mL) was added hydrazine hydrate (1.8 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (1×2 mL) andwater (2×2 mL), and drying under vacuo at rt for 72 hrs gave 619 mg ofthe title compound (75%) as a white solid in 99.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.34 (s, 1H), 9.66 (s, 1H), 7.87 (d, J=8.1Hz, 2H), 7.82 (m, 4H), 7.34 (d, J=8.1 Hz, 2H), 4.43 (s, 2H), 2.64 (t,J=7.6 Hz, 2H), 1.58 (m, 2H), 1.25 (m, 8H), 0.84 (t, J=6.6 Hz, 3H).

c) Preparation of4-Heptyl-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-heptyl-N-[4-(hydrazinocarbonyl)phenyl]-benzamide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 111 mg of the title compound(91%) as a yellow powder in 93.1% purity by HPLC (R_(t): 6.3, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 306° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 11.46 (s, 1H), 10.53 (s, 1H),8.02 (d, J=8.7 Hz, 2H), 7.89 (m, 4H), 7.84 (d, J=1.5 Hz, 1H), 7.71 (dd,J=8.3, 1.5 Hz, 1H), 7.36 (d, J=8.2 Hz, 2H), 6.81 (d, J=8.3 Hz, 1H), 2.65(t, J=7.6 Hz, 2H), 1.59 (m, 2H), 1.26 (m, 8H), 0.85 (t, J=6.8 Hz, 3H).

M⁻(APCI⁻): 607; M⁺(APCI⁺): 609.

Example 402-(2-Nitro-4,5-dimethoxyphenyl)-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-yliden)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3one in acetic acid was added2-(3-nitro-4,5-dihydroxyphenyl)acetohydrazide. After stirring at 100° C.the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 78 mg of the title compound (76%) as ayellow powder in 90.6% purity by HPLC (R_(t): 4.49, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 307° C. (decomp.).

M⁻(APCI⁻): 509; M⁺(APCI⁺): 511.

Example 41N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1-(3-pyridinylmethyl)-4-piperidinecarbohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[1-(3-pyrdinylmethyl)-4-piperidinyl]acetohydrazide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 72 mg of the title compound(74%) as a yellow powder in 86.8% purity by HPLC (R_(t): 2.02, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 125° C.

M⁻(APCI⁻): 488; M⁺(APCI⁺): 490.

Example 42N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)2-amino-5-nitro-benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-amino-5-nitrobenzohydrazide. After stirring at 100° C. the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 69 mg of the title compound (76%) as a yellow powder in98.8% purity by HPLC (R_(t): 4.22, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 344° C. (decomp.).

M⁻(APCI⁻): 450.

Example 432-[5-(3-Nitrophenyl)-2H-tetrazol-2-yl]-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[5-(3-nitrophenyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 80 mg of the title compound(77%) as a yellow powder in 97% purity by HPLC (R_(t): 4.96, gradient of8 min, MaxPlot detection between 230 and 400 nm).

M.p. 254° C. (decomp.).

M⁻(APCI⁻): 517.

Example 44N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(1pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[5-(1-pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 67 mg of the title compound(72%) as a yellow powder in 95% purity by HPLC (R_(t): 4.24, gradient of8 min, MaxPlot detection between 230 and 400 nm).

M.p. 265° C. (decomp.).

M⁻(APCI⁻): 465; M⁺(APCI⁺): 467.

Example 45N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 73 mg of the title compound(76%) as a yellow powder in 86.7% purity by HPLC (R_(t): 3.84, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 253° C. (decomp.).

M⁻(APCI⁻): 481; M⁺(APCI⁺): 483.

Example 464-{2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoicacid a) Preparation of 4-(2-hydrazino-2-oxoethoxy)benzoic acid (compoundC, Scheme 2)

In an Parr autoclave, a solution of benzyl4-(2-hydrazino-2-oxoethoxy)benzoate (400 mg, 1.3 mmol) and a catalyticamount Pd/C in AcOH (25 mL) was stirred under hydrogen pressure (5 Bars)at rt for 45 min. After filtration over celite, the filtrate wasevaporated off. The residue was taken up in MeOH and a beige solidprecipitated out. Filtration and drying under vacuo at 50° C. overnightgave the title compound as a beige solid (118 mg) in a 42% yield.

¹H NMR (DMSO-d₆/CD₃OD (35/1), 300 MHz) δ 7.87 (m, 2H), 7.06 (d, J=8.6Hz, 0.5H), 7.00 (d, J=8.6 Hz, 0.5H), 6.93 (d, J=8.6 Hz, 1H), 5.05 (s,1H), 4.71 (s, 1H).

b) Preparation of4-{2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoicacid

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(2-hydrazino-2-oxoethoxy)benzoic acid. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 6 mg of the title compound (7%) as a yellowsolid in 97.8% purity by HPLC (R_(t): 3.63, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.62 (br s, 0.6H), 12.64 (br s, 1H), 12.48(br s, 0.4H), 11.36 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.84 (br s, 1H),7.71 (dd, J=8.3, 1.9 Hz, 1H), 7.11 (d, J=8.1 Hz, 2H), 6.80 (d, J=8.3 Hz,1H), 5.39 (br s, 0.8H), 4.97 (br s, 1.2H).

M⁻(APCI⁻): 464.

Example 474-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-phenylbenzamidea) Preparation of 4-(hydrazinoarbonyl-N-phenylbenzamide (Scheme 2,compound B)

To a suspension of methyl 4-(anilinocarbonyl)benzoate (634 mg, 2.48mmol) in EtOH (8 mL) was added hydrazine hydrate (1.81 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (3×3 mL) andwater (3×3 mL), and drying under vacuo at 60° C. for 2 hrs gave 548 mgof the title compound (86%) as a white solid in 96.3% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.33 (s, 1H), 9.93 (s, 1H), 8.00 (d, J=8.3Hz, 2H), 7.94 (d, J=8.3 Hz, 2H), 7.77 (d, J=7.7 Hz, 2H), 7.35 (dd,J=7.7, 7.4 Hz, 2H), 7.10 (t, J=7.4 Hz, 1H), 4.55 (s, 2H).

b) Preparation of4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-phenylbenzamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(hydrazinoarbonyl)-N-phenylbenzamide. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 198 mg of the title compound (71%) as a yellowpowder in 94.6% purity by HPLC (R_(t): 4.48, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 374° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.87 (s, 1H), 11.49 (s, 1H), 10.44 (s, 1H),8.14 (d, J=8.3 Hz, 2H), 8.02 (d, J=8.3 Hz, 2H), 7.84 (br s, 1H), 7.78(d, J=7.9 Hz, 2H), 7.73 (dd, J=7.9, 1.5 Hz), 7.37 (dd, J=7.9, 7.4 Hz,2H), 7.12 (t, J=7.4 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H).

M⁻(APCI⁻): 509; M⁺(APCI⁺): 511.

Example 484-Cyano-N-(3-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamidea) Preparation of methyl 3-[(4-cyanobenzoyl)amino]benzoate (compound C,Scheme 2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anydrouspyridine (10 mL) was added dropwise 4-cyanobenzoyl chloride (660 mg, 4.0mmol) at 0° C. After 5 min the temperature was allowed to warm up to rt.After 3 hrs aminomethyl resin (Polymers Laboratories PL-AMS, 1.96mmol/g, 720 mg) was added and the resulting mixture was stirredovernight at rt. After rinsing the resin and filtration, water (25 mL)was added to the filtrate and a beige solid precipated out. Filtrationand washing with water gave a solid which was dried under vacuo at 60°C. for 5 hrs. The title compound (774 mg) was obtained as a beige solid(83%) in 97.7% purity by HPLC (MaxPlot detection between 230 and 400 nm)¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 8.45 (m, 1H), 8.12 (d, J=8.3Hz, 2H), 8.05 (m, 3H), 7.71 (d, J=7.8 Hz, 1H), 7.52 (dd, J=7.9, 7.8 Hz,1H), 3.86 (s, 3H).

b) Preparation of 4-cyano-N-[3-(hydrazinocarbonyl)phenyl]benzamide(compound B, Scheme 2)

To a suspension of methyl 3-[(4-cyanobenzoyl)amino]benzoate (762 mg,2.72 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.79 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (3 mL) andwater (3×3 mL) and drying under vacuo at 60° C. for 2 hrs gave 518 mg ofthe title compound (68%) as a white solid in 98.8% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.61 (s, 1H), 9.76 (s, 1H), 8.22 (s, 1H),8.12 (d, J=8.2 Hz, 2H), 8.03 (d, J=8.2 Hz, 2H), 7.3 (d, J=7.7 Hz, 1H),7.5 (d, J=7.8 Hz, 1H), 7.42 (dd, J=7.8, 7.7 Hz, 1H), 4.48 (s, 2H).

c) Preparation of4-Cyano-N-(3-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]-carbonyl}phenyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-cyano-N-[3-hydrazinocarbonyl)phenyl]benzamide. After stirring at 100°C. the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 181 mg of the title compound (61%) as aorange powder in 96.5% purity by HPLC (R_(t): 4.4, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 309° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 11.45 (s, 1H), 10.77 (s, 1H),8.45 (s, 1H), 8.10 (m, 5H), 7.86 (s, 1H), 7.72 (br d, J=8.3 Hz, 1H),7.61 (m, 2H), 6.81 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 534; M⁺(APCI⁺): 536.

Example 49N′-[5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-4-[4-(4-morpholinyl-methyl)phenoxy]benzohydrazidea) Preparation of methyl 4-[4(bromomethyl)phenoxy]benzoate (Compound Cof Scheme 2)

At 10° C. a mixture of HBr (400 mL) and sulfuric acid (20 mL) was addeda solution of methyl 4-[4-(bromomethyl)phenoxy]benzoate (100 g) in1,2-dichloroethane. Then the reaction mixture was allowed to stir at 60°C. for 3 hrs. After extraction the organic layer was washed with waterand a saturated aqueous solution of NaHCO₃. Drying over sodium sulfateand evaporation under vacuo gave the title compound (110 g) in a 88%yield.

b) Preparation of methyl 4-[4-(morpholinylmethyl)phenoxy benzoate(Compound C of Scheme 2)

To a stirred solution of morpholine (10.7 g, 0.12 mol) and methyl amine(35 mL, 0.21 M) in absolute alcohol (550 mL) was added methyl4-[4-(bromomethyl)phenoxy)]benzoate (55 g, 0.17 mol) in 250 mL of dryTHF. The reaction mixture was allowed to stir overnight at rt. Then thereaction mixture was concentrated and the residue was tretaed with HCl(4N). The acidic mixture was washed with diethyl ether to remove organicimpurities and basified using an aqueous solution of NaHCO₃ (10%).Further extraction with diethyl ether, washing with brine and dryingunder vacuo gave the title compound (34 g) in a 87% yield.

¹H NMR (300 MHz, DMSO-d₆) δ 7.92 (d, J=7.7 Hz, 2H), 7.39 (d, J=7.7 Hz,2H), 7.1 (m, 4H), 3.82 (s, 3H), 3.58 (m, 4H), 3.47 (s, 2H), 2.38 (m,4H).

c) Preparation of 4-[4-(1,3-oxazinan-3-ylmethyl)phenoxy]benzohydrazide(Scheme 2, compound B)

To a suspension of methyl 4-(4-(morpholinylmethyl)phenoxy benzoate (1309mg, 4.00 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.46 mL).After stirring for 18 h at reflux, the reaction mixture was cooled to rtand poured into water (20 mL). A white solid precipitated out.Filtration, washing with water (3×3 mL) and drying under vacuo at 60° C.for 4 hrs gave 919 mg of the title compound as a white solid in a 70%yield.

¹H NMR (DMSO-d₆, 300 MHz) δ 9.67 (s, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.34(d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 6.98 (d, J=9.0 Hz, 2H), 4.45(s, 2H), 3.56 (m, 4H), 3.44 (s, 2H), 2.34 (m, 4H).

d) Preparation ofN′-[5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-4-[4-(4-morpholinyl-methyl)phenoxy]benzohydrazide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-[4-(1,3-oxazinan-3-ylmethyl)phenoxy]benzohydrazide. After stirring at100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 194 mg of the title compound(67%) as a yellow solid in 98.9% purity by HPLC (R_(t): 3.27, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 252° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.79 (s, 1H), 11.46 (s, 1H), 7.90 (d, J=8.8Hz, 2H), 7.83 (d, J=1.5 Hz, 1H), 7.71 (dd, J=8.3, 1.5 Hz, 1.5), 7.38 (d,J=8.5 Hz, 2H), 7.14 (d, J=8.8 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.80 (d.,J=8.3 Hz, 1H), 3.57 (m, 4H), 3.47 (s, 2H), 2.36 (m, 4H).

M⁻(APCI⁻): 581; M⁺(APCI⁺): 583.

Example 50N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)benzamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]benzamide. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 114 mg of the title compound (89%) as a yellowpowder in 96.3% purity by HPLC (R_(t): 4.4, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 338° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.85 (s, 1H), 11.47 (s, 1H), 10.62 (s, 1H),8.00 (m, 4H), 7.90 (d, J=8.6 Hz, 2H), 7.83 (d, J=1.5 Hz, 1H), 7.71 (dd,J=8.2, 1.5 Hz, 1H), 7.59 (m, 3H), 6.81 (d, J=8.2 Hz, 1H).

M⁻(APCI⁻): 509.

Example 514-(Benzyloxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(benzyloxy)benzohydrazide. After stirring at 100° C., the reactionmixture was cooled to rt and a yellow solid precipitated out. Filtrationon a fritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 247 mg of the title compound (90%) as a yellow powder in98.9% purity by HPLC (R_(t): 5.03, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M.p. 298° C.

IR (neat) v 3240, 1693, 1667, 1603, 1494, 1448, 1244, 1172, 1140, 1121,1025, 916 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.80 (s, 1H), 11.46 (s, 1H), 7.86 (d, J=8.8Hz, 2H), 7.81 (br s, 1H), 7.70 (dd, J=8.3, 1.5 Hz, 1H), 7.48-7.42 (m,5H), 7.22 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.3 Hz, 1H), 5.22 (s, 2H).

M⁻(ESI (LC/MS)⁻): 496; M⁺(ESI (LC/MS)⁺): 498.

Example 52N-(3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-3-phenylpropanamidea) Preparation of N-[3-hydrazinocarbonyl)phenyl]-3-phenylpropanamide(Scheme 2, compound B)

To a suspension of methyl 3-[(3-phenylpropanoyl)amino]benzoate (623 mg,2.20 mmol) in EtOH (8 mL) was added hydrazine hydrate (1.79 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt antreated with water (30 mL). A white solid precipitated out. Filtration,washing with water (3×3 mL) and drying under vacuo at 60° C. for 2 hrsgave 377 mg of the title compound (65%) as a white solid in 95.8% purityby HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.03 (s, 1H), 9.69 (s, 1H), 7.98 (s, 1H),7.74 (d, J=7.7 Hz, 1H), 7.43 (d, J=7.6 Hz, 1H), 7.35-7.17 (m, 6H), 4.47(s, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.62 (t, J=7.6 Hz, 2H).

b) Preparation ofN-(3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-3-phenylpropanamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[3-hydrazinocarbonyl)phenyl]-3-phenylpropanamide. After stirring at100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 210 mg of the title compound(78%) as a yellow powder in 96.95% purity by HPLC (R_(t): 4.53, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 293° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.80 (s, 1H), 11.46 (s, 1H), 10.23 (s, 1H),8.23 (s, 1H), 7.85 (m, 2H), 7.72 (dd, J=8.3, 1.5 Hz, 1H), 7.53 (m, 2H),7.28 (m, 4H), 7.18 (m, 1H), 6.81 (d, J=8.3 Hz, 1H), 2.93 (t, J=7.6 Hz,2H), 2.66 (t, J=7.6 Hz, 2H).

M⁻(APCI⁻): 537.

Example 534-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamidea) Preparation of methyl4-({3-[(trifluoromethyl)sulfonyl]anilino}carbonyl)benzoate (Compound Cof Scheme 2)

To a solution of 3-aminophenyltrifluoromethylsulfone (750 mg, 3.33 mmol)in anhydrous DMF (10 mL) were added DIEA (0.7 mL, 4 mmol) andterephtalic acid monomethyl ester chloride (794 mg, 4 mmol) at 0° C.After 5 min the reaction mixture was allowed to warm up to rt. After 1hr, water (5 mL) was added and the resulting reaction mixture wasallowed to stir at rt overnight The reaction mixture was poured intowater (100 mL) and a brown solid precipitated out. Filtration andwashing with water (3×5 mL) of the solid gave a residue which waspurified by flash chromatography using EtOAc/cyclohexane as eluant Thetitle compound was collected as a white solid (390 mg, 30%) in a 99.8%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.68 (br s, 1H), 8.38 (m,1H), 8.11 (s, 4H), 7.86 (m, 2H), 3.89 (s, 3H). M⁻(APCI⁻): 386.

b) Preparation of4-(hydrazinocarbonyl)-N-{3-[(trifluoromethyl)sulfonyl]phenyl}-benzamide(Scheme 2 compound B)

To a suspension of methyl4-({3-[(trifluoromethyl)sulfonyl]anilino}carbonyl)benzoate (390 mg, 1.1mmol) in EtOH (6 mL) was added hydrazine hydrate (1 mL). After stirringfor 15 hrs at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out Filtration, washing with EtOH (1×1 mL) and water(3×1 mL), and drying under vacuo at 60° C. for 2 hrs gave 247 mg of thetitle compound (63%) as a white solid in 95% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.89 (s, 1H), 9.95 (s, 1H), 8.69 (s, 1H),8.38 (n, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.97 (d, J=8.4 Hz, 2H), 7.86 (m,2H), 4.58 (s, 2H).

c) Preparation of4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-(hydrazinocarbonyl)-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 80 mg of thetitle compound (76%) as a yellow solid in 76% purity by HPLC (R_(t):4.96, gradient of 8 min, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.88 (s, 1H), 11.50 (s, 1H), 11.01 (s, 1H),8.69 (s, 1H), 8.38 (m, 1H), 8.19 (d, J=8.3 Hz, 2H), 8.05 (d, J=8.3Hz,2H), 7.86 (m, 3H), 7.73 (dd, J=8.3, 1.5 Hz, 1H), 6.82 (d, J=8.3 Hz, 1H).

M⁻(ESI⁻): 641.

Example 544-Chloro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)benzamidea) Preparation of methyl 4-{[(4-chlorobenzoyl)amino]methyl}benzoate(Compound C of Scheme 2)

To a stirred solution of methyl 4-(aminomethyl)benzoate (75 g, 0.46 mol)and TEA (315 mL, 2.27 mol) in anhydrous DCM (1.5 L) was added a solutionof freshly prepared 4-chloro benzoyl chloride (0.91 mol) in DCM (400mL). The resulting mixture was allowed to stir for 12 hrs. The reactionwas quenched with a 10% aqueous solution of sodium hydrogenocarbonate.The organic layer was washed with a 1.5N HCl solution and water. Afterdrying over MgSO₄ and evaporation of the solvent in vacuo, a solid wasobtained. Recrystallization form MeOH gave the title compound (80 g) ina 60% yield as a white powder.

¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (t, J=5.23 Hz, 1H), 7.92 (dd, J=7.0,1.7 Hz, 4H), 7.58 (d, J=7.0 Hz, 2H), 7.45 (d, J=7.0 Hz, 2H), 4.57 (d,J=4.5 Hz, 2H), 3.86 (s, 3H).

b) Preparation of 4-chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide(Scheme 2, compound B)

To a suspension of methyl 4-{[(4-chlorobenzoyl)amino]methyl}benzoate(303 mg, 1.0 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.0 mL).After stirring for 15 h at reflux, the reaction mixture was cooled to rtand a white solid precipitated out. Filtration, washing with water (3×2mL) and drying under vacuo at 60° C. for 2 hrs gave 213 mg of the titlecompound (70%) as a white solid in 96.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 9.69 (s, 1H), 9.16 (br s, 1H), 7.90 (d,J=7.9 Hz, 2H), 7.76 (d, J=7.9 Hz, 2H), 7.55 (d, J=7.9 Hz, 2H), 7.35 (d,J=7.9 Hz, 2H), 4.50 (d, J=5.3 Hz, 2H), 4.44 (s, 2H).

c) Preparation of4-Chloro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-chloro-N-[4-(hydrazinocarbonyl)benzyl]benzamide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 126 mg of the title compound(92%) as a yellow solid in 89.18% purity by HPLC (R_(t): 4.48, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.46 (s, 1H), 9.23 (t, J=5.3Hz, 1H), 7.88 (m, 5H), 7.71 (d, J=8.3 Hz, 1H), 7.55 (m, 4H), 6.81 (d,J=8.3 Hz, 1H), 4.57 (d, J=5.3 Hz, 1H).

M⁻(ESI⁻): 557; M⁺(ESI⁺): 559.

Example 55 Methyl4-{3-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzoatea) Preparation of methyl 3-(3-hydrazino-3-oxopropyl)benzoate (Compound Cof Scheme 2)

To a suspension of methyl 4-(3-methoxy-3-oxopropyl)benzoate (500 mg,2.25 mmol) in MeOH (10 mL) was added hydrazine hydrate (1.09 mL). Afterstirring for 18 h at rt, the reaction mixture was poured into water (30mL). The solvent was evaporated off until a final volume of 5 mL and awhite solid precipitated out. Filtration and drying under vacuo at 70°C. overnight gave a white solid which was identified as methyl3-(3-hydrazino-3-oxopropyl)benzoate (38 mg, 8%) [¹H NMR (300 MHz,DMSO-d₆) δ 8.95 (s, 1H), 7.85 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.9 Hz, 2H),4.17 (s, 2H), 3.82 (s, 3H), 2.87 (t, J=7.7 Hz, 2H), 2.33 (t, J=7.7 Hz,2H)]. And the filtrate was evaporated off under vacuo. The white residuewas washed with MeOH and dryed under vacuo at 70° C. overnight to give4-(3-hydrazino-3-oxopropyl)benzohydrazide (278 mg, 56%) [¹H NMR (300MHz, DMSO-d₆) δ 9.66 (s, 1H), 8.94 (s, 1H), 7.71 (d, J=8.3 Hz, 2H), 7.25(d, J=8.3 Hz, 2H), 4.43 (s, 2H), 4.14 (s, 2H), 2;84 (t, J=7.8 Hz, 2H),2.32 (t, J=7.8 Hz, 2H)].

b) Preparation of methyl4-{3-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl3-(3-hydrazino-3-oxopropyl)benzoate. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 42 mg of the title compound (60%) as a yellowpowder in 86% purity by HPLC (R_(t): 4.56, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M⁻(APCI⁻): 476.

Example 562-[(2-Chlorophenoxy)methyl]-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4carbohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-[(2-chlorophenoxy)methyl]-1,3-thiazole-4-carbohydrazide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 47 mg of the titlecompound (79%) as a orange powder in 98.2% purity by HPLC (R_(t): 5.07,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 537; M⁺(ESI (LC/MS)⁺): 539.

Example 57N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(2-phenyl[1,3]thiazolo-[3.2-b][1,2,4]triazol-6-yl)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-(2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazol-6-yl)acetohydrazide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 28 mg of the titlecompound (48%) as a yellow powder in 94.7% purity by HPLC (R_(t): 4.65,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 527; M⁺(ESI (LC/MS)⁺): 529.

Example 584-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]butanohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-{[3-methyl-5-(trifluoromethyl)-2-pyridinyl]amino}butanohydrazide.After stirring at 100° C. the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 5 mg of thetitle compound (8%) as a yellow powder in 98.1% purity by HPLC (R_(t):5.23, gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 550; M⁺(ESI (LC/MS)⁺): 552.

Example 592-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added2-{[3-methyl-5-(trifluoromethyl)-2-pyridinyl]amino}acetohydrazide. Afterstirring at 100° C. the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 38 mg of the titlecompound (66%) as a orange powder in 98.5% purityby HPLC (R_(t): 5.1,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 522; M⁺(ESI (LC/MS)⁺): 524.

Example 601-Benzoyl-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-piperidinecarbohydrazidea) Preparation of (±)-1-benzoyl-4-piperidinecarbohydrazide (Scheme 2,compound B)

To a suspension of (±)-methyl 1-benzoyl-4-piperidinecarboxylate (502 mg,2.03 mmol) in MeOH (10 mL) was added hydrazine hydrate (1.6 mL). Afterstirring for 24 h at rt, the reaction mixture and water (40 mL) wasadded. After washing with Et₂O (2×20 mL), the aqueous layer wasevaporated off under vacuo. The title compound was obtained as anamorphous beige solid (469 mg, 93%) in a 91.0% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 9.01 (s, 1H), 7.43 (m, 3H), 7.35 (m, 2H),4.60-3.20 (m, 4H), 3.10-2.65 (m, 2H), 2.34 (m, 1H), 1.81-1.52 (m, 4H).

b) Preparation of1-Benzoyl-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-piperidinecarbohydrazide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added(±)-1-benzoyl-4-piperidinecarbohydrazide. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 221 mg of the title compound (88%) as a yellowsolid in 94.1% purity by HPLC (R_(t): 3.93, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 160° C.

M⁻(APCI⁻): 501; M⁺(APCI⁺): 503.

Example 61N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-2-phenoxyacetamidea) Preparation of N-[4-(hydrazinocarbonyl)phenyl]-2-phenoxyacetamide(Scheme 2, compound B)

To a suspension of methyl 4-[(phenoxyacetyl)amino]benzoate (843 mg, 2.95mmol) in EtOH (10 mL) was added hydrazine hydrate (2.15 mL). Afterstirring for 15 hrs at reflux, the reaction mixture was cooled to rt.Water (10 mL) was added to the reaction mixture and a white solidprecipitated out. Filtration, washing with EtOH/water (2×2 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 6 hrs gave 389 mg of thetitle compound (46%) as a white solid in 95.4% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.28 (s, 1H), 9.65 (s, 1H), 7.79 (d, J=8.3Hz, 2H), 7.69 (d, J=8.3 Hz, 2H), 7.31 (m, 2H), 6.98 (m, 3H), 4.71 (s,2H), 4.42 (s, 2H).

b) Preparation ofN-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-2-phenoxyacetamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]-2-phenoxyacetamide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 222 mg of the title compound(82%) as a yellow solid in 98.1% purity by HPLC (R_(t): 4.41, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 305° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.46 (s, 1H), 10.50 (s, 1H),7.87(s, 4H), 7.83 (br s, 1H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 7.31 (m,2H), 6.98 (m, 3H), 6.81 (d, J=8.3 Hz, 1H), 4.75 (s, 2H).

M⁻(APCI⁻): 539; M⁺(APCI⁺): 541.

Example 62N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)nicotinamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-hydrazinocarbonyl)phenyl]nicotinamide. After stirring at 100° C.the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 181 mg of the title compound (71%) as aorange solid in 96.8% purity by HPLC (R_(t): 3.01, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 344° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.85 (s, 1H), 11.47 (s, 1H), 10.81 (s, 1H),9.13 (d, J=1.9 Hz, 1H), 8.78 (dd, J=4.9, 1.5 Hz, 1H), 8.32 (dd,d, J=7.9,1.9, 1.5 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.92 (d, J=8.7 Hz, 2H), 7.83(br s, 1H), 7.72 (dd, J=7.9, 1.5 Hz, 1H), 7.59 (dd, J=7.9,4.9 Hz, 1H),6.82 (d, J=7.9 Hz, 1H).

M⁻(APCI⁻): 510; M⁺(APCI⁺): 512.

Example 633-(Nitro)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}benzyl)benzamidea) Preparation of methyl 4-{[(3-nitrobenzoyl)amino]methyl}benzoate(Sheme 2, compound C)

Under an inert atmosphere, to a stirred solution of methyl4-(aminomethyl)benzoate (50 g, 0.436 mol) and TEA (210 mL, 1.5 mol) inanhydrous DCM (1.0 L) was added a solution of freshly prepared 3-nitrobenzoyl chloride (0.59 mol) in DCM (250 mL). The resulting mixture wasallowed to stir for 2 hrs. The reaction was quenched with a 10% aqueoussolution of sodium hydrogenocarbonate. The organic layer was washed witha 1.5N HCl solution and water. After drying over MgSO₄ and evaporationof the solvent in vacuo, a solid was obtained and purified by flashchromatography to give the title compound (50 g) in a 52% yield as awhite powder.

¹H NMR (300 MHz, DMSO-d₆) δ 9.51 (t, J=5.7 Hz, 1H), 8.73 (t, J=1.9 Hz,1H), 8.41 (ddd, J=8.3, 2.0, 0.7 Hz, 1H), 8.34 (d, J=7.9 Hz, 1H), 7.93(d, J=8.3 Hz, 2H), 7.79 (t, J=8.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 4.59(d, J=5.7Hz, 2H), 3.83 (s, 3H).

b) Preparation of N-[4-(hydrazinocarbonyl)benzyl]-3-nitrobenzamide(Sheme 2, compound B)

To a suspension of 4-{[(3-nitrobenzoyl)amino]methyl}benzoate (500 mg,1.59 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.16 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (2×2 mL),EtOH/water (2×2 mL)and water (2×2 mL), and drying under vacuo at 70° C.for 5 hrs gave 379 mg of the title compound (76%) as a pale yellow solidin 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.47 (t, J=5.7 Hz, 1H), 8.73(s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.33 (d, J=7.5 Hz, 1H), 7.79 (m, 3H),7.39 (d, J=8.3 Hz, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.45 (s, 2H).

c) Preparation of3-(Nitro)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}benzyl)benzamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)benzyl]-3-nitrobenzamide. After stirring at 100°C. the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 252 mg of the title compound (89%) as aorange solid in 95.4% purity by HPLC (R_(t): 4.15, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 331° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.46 (s, 1H), 9.54 (t, J=5.6Hz, 1H), 8.75 (br s, 1H), 8.40 (dd, J=7.9, 1.2 Hz, 1H), 8.35 (d, J=8.0Hz, 1H), 7.87 (d, J=8.3 Hz, 2H), 7.83 (br s, 1H), 7.80 (dd, J=8.0, 7.9Hz, 1H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 7.57 (d, J=8.3 Hz, 2H), 6.80 (d,J=8.3 Hz, 1H), 4.61 (d, J=5.6 Hz, 2H).

M⁻(APCI⁻): 568; M⁺(APCI⁺): 570.

Example 64N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)[1,1′-biphenyl]-4-carboxamidea) Preparation ofN-[4-(hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide (Scheme 2,compound B)

To a suspension of methyl4-[([1,1′-biphenyl]-4-ylcarbonyl)amino]benzoate (880 mg, 2.66 mmol) inEtOH (10 mL) was added hydrazine hydrate (1.8 mL). After stirring for 7days at reflux, the reaction mixture was cooled to rt and a white solidprecipitated out. Filtration, washing with EtOH (3×2 mL) and water (3×2mL), and drying under vacuo at rt for 6 hrs gave 585 mg of the titlecompound (66%) as a white solid in 96.4% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.48 (s, 1H), 9.67 (s, 1H), 8.06 (d, J=8.6Hz, 2H), 7.85 (m, 6H), 7.76 (m, 2H), 7.51 (m, 2H), 7.42 (m, 1H), 4.46(s, 2H).

b) Preparation ofN-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)[1,1′-biphenyl]-4-carboxamide(Compound C of Scheme 2)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl][1,1′-biphenyl]-4-carboxamide. Afterstirring at 100° C. the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 243 mg of the titlecompound (83%) as a yellow powder in 95.7% purity by HPLC (R_(t): 5.34,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 349° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.85 (s, 1H), 11.47 (s, 1H), 10.67 (s, 1H);8.08 (d, J=8.3 Hz, 2H), 8.04 (d, J=8.8 Hz, 2H), 7.91 (d, J=8.8 Hz, 2H),7.86 (m, 3H), 7.76 (m, 2H), 7.71 (dd, J=8.3, 1.9 Hz, 1H), 7.51 (m, 2H),7.42 (m, 1H), 6.82 (d, J=8.3 Hz, 1H).

M⁻(APCI⁻): 585; M⁺(APCI⁺): 587.

Example 65 Methyl3-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoatea) Preparation of methyl 3-(2-hydrazino-2-oxoethoxy)benzoate (Compound Cof Scheme 2)

To a suspension of methyl 3-(2-methoxy-2-oxoethoxy)benzoate (887 mg,3.96 mmol) in MeOH (50 mL) was added hydrazine hydrate (1.92 mL). Afterstirring for 0.5 h at rt, water (50 mL) was added and the reactionmixture was filtered. Washing with water (3×5 mL) and drying under vacuoat 70° C. overnight gave 713 mg of the title compound (80%) as a whitesolid in 98.3% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 9.38 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.50(br s, 1H), 7.44 (dd, J=8.3, 7.5 Hz, 1H), 7.24 (dd, J=8.3, 1.5 Hz, 1H),4.55 (s, 2H), 4.32 (s, 2H), 3.84 (s, 3H).

b) Preparation of methyl3-{2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]-2-oxoethoxy}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added methyl3-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C. thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 380 mg of the title compound (79%) as a orangepowder in 98.9% purity by HPLC (R_(t): 4.3, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M.p. 237° C.

IR (neat) v 3173, 1715, 1690, 1431, 1243, 1206, 1137, 752 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.64 (br s, 0.6), 12.48 (br s, 0.4H), 11.36(s, 1H), 7.82 (br s, 1H), 7.70 (dd, J=8.3, 1.9 Hz, 1H), 7.62-7.46 (m,3H), 7.33 (m, 1H), 6.79 (d, J=8.3 Hz, 1H), 5.40 (br s, 0.8H), 4.97 (brs, 1.2 H), 3.85 (s, 3H).

M⁻(APCI⁻): 478; M⁺(APCI⁺): 480.

Example 66 Methyl4-{[[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-3-ylidene)hydrazino]-(oxo)acetyl]amino}benzoatea) Preparation of methyl 3-{[methoxy(oxo)acetyl]amino}benzoate (CompoundC of Scheme 2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anydrouspyridine (10 mL) was added dropwise methyl chlorooxoacetate (370 μL,3.97 mmol) at 0° C. After 5 min the temperature was allowed to warm upto rt. After 90 min, aminomethyl resin (Polymers Laboratories PL-AMS,1.96 mmol/g, 720 mg) was added and the resulting mixture was stirredovernight at rt. After filtration and rinsing the resin, water (50 mL)was added into the filtrate and a white solid precipated out. Filtrationand washing with water gave a solid which was dried under vacuo at 70°C. for 5 hrs. The title compound (554 mg) was obtained as a white solid(71%) in 99.6% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (300 MHz, DMSO-d₆) δ 11.09 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.90(d, J=8.6 Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H).

b) Preparation of methyl 3-{[hydrazino(oxo)acetyl]amino}benzoate (Scheme2, compound B):

To a suspension of methyl 3-{[methoxy(oxo)acetyl]amino}benzoate (100 mg,0.42 mmol) in MeOH (8 mL) was added hydrazine hydrate (0.2 mL). Afterstirring for 0.5 h at rt, the reaction mixture was filtered. Washingwith MeOH (2×1 mL) and water (3×1 mL) and drying under vacuo at 70° C.for 2 hrs gave 82 mg of the title compound (82%) as a white solid in97.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.91 8s, 1H), 10.33 (s, 1H), 7.97 (d, J=9.0Hz, 2H), 7.92 (d, J=9.0 Hz, 2H), 4.64 (s, 2H), 3.82 (s, 3H).

c) Preparation of Methyl4-{[[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-(oxo)acetyl]amino}benzoate

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was addedmethyl 3-{[hydrazino(oxo)acetyl]amino}benzoate. After stirring at 100°C. the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 123 mg of the title compound (83%) as aorange solid in 94.45% purity by HPLC (R_(t): 4.19, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 364° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 14.15 (s, 1H), 11.43 (s, 1H), 11.36 (s, 1H),8.00 (m, 4H), 7.86 (s, 1H), 7.74 (d, J=7.9 Hz, 1H), 6.80 (d, J=7.9 Hz,1H), 3.83 (s, 3H).

M⁻(APCI⁻): 491.

Example 673-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamidea) Preparation of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (Compound C ofScheme 2)

To a solution of 3-(3,4-methylenedioxyphenyl)-propionic acid (501 mg,2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C.After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg,2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture.After 30 min the temperature was allowed to warm up to rt and stir for24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50mL) and a saturated aqueous solution of NaHCO₃ (50 mL), the organiclayer was dryed over sodium sulfate and evaporated under vacuo to give asolid. The residue was taken up in Et₂O, filtrated and washed with Et₂Ogave the title compound as a white solid (62%) in a 99.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.22 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.70(d, J=8.7 Hz, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.68(dd, J=7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 3.80 (s, 3H), 2.82 (t, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H).

b) Preparation of3-(1,3-benzodioxol-5-yl)-N-[4-hydrazinocarbonyl)phenyl]propanamide(Scheme 2, compound B)

To a suspension of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol)in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirringfor 15 hrs at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out. Filtration, washing with EtOH (2×1 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of thetitle compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).¹H NMR (DMSO-d₆, 300 MHz) δ 10.08 (s,1H), 9.60 (s, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 6.82(d, J=1.5 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.68 (dd, J=7.9, 1.5 Hz, 1H),5.94 (s, 2H), 4.41 (s, 2H), 2.82 (t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz,2H).

c) Preparation of3-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide.After stirring at 100° C. the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 97 mg of thetitle compound (76%) as a yellow solid in 98.8% purity by HPLC (R_(t):4.33, gradient of 8 min, MaxPlot detection between 230 and 400 nm).

M.p. 314° C. (decomp.).

IR (neat) v (cm⁻¹) 3188, 1720, 1655, 1593, 1488, 1245, 1119, 1039, 918and 812.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.29 (s, 1H),7.82 (m, 5H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 6.81 (m, 3H), 6.70 (dd,J=7.9, 1.1 Hz, 1H), 5.95 (s, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.5Hz, 2H).

M⁻(ESI (LC/MS)⁻): 581; M⁺(ESI (LC/MS)⁺): 583.

Example 684-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzoyl)amino]benzoicacid a) Preparation of 4-{[4-(methoxycarbonyl)benzoyl]amino}benzoic acid(Compound C of Scheme 2)

To a solution of 4-aminobenzoic acid (500 mg, 3.65 mmol) in anhydrousTHF (20 mL) were added DIEA (1.36 mL, 8.02 mmol) andtert-butyldimethylchlorosilane (4 mL, 1M in THF). The resulting mixturewas allowed to stir at rt for 45 min. A solution of terephtalic acidmonomethyl ester chloride (800 mg, 4 mmol) in THF (5 mL) was added andthe resulting mixture was stirred for 90 min at rt until thedisappearance of the starting material and finally TBAF (4 mL, 1M inTHF) was added. After 25 min at rt, the reaction was quenched with asolution of 0.1N HCl (100 mL). Extraction with EtOAc (3×200 mL), dryingover sodium sulfate and evaporation under vacuo gave a pale yellowsolid. Washing with hot EtOH (50 mL) gave the tilte compound as a whitesolid (698 mg, 64%) in a 84% purity by HPLC (MaxPlot detection between230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 12.77 (s, 1H), 10.71 (s, 1H), 8.09 (m, 4H),7.95 (d, J=9.0 Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 3.89 (s, 3H).

b) Preparation of 4-{[4-(hydrazinocarbonyl)benzoyl]amino}benzoic acid(Scheme 2, compound B)

To a suspension of 4-{[4-(methoxycarbonyl)benzoyl]amino}benzoic acid(300 mg g, 1 mmol) in EtOH (4.5 mL) was added hydrazine hydrate (0.73mL). After stirring for 15 h at reflux, the reaction mixture was cooledto rt and a white solid precipitated out. Filtration, washing with EtOH(3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave a white solid.This residue was taken up in water (25 mL) and AcOH (5 mL) was added. Awhite solid precipitated out which was further washed with water (3×2mL). Drying at 80° C. for 1 hr gave 220 mg of the title compound (73%)as a white solid in 91.2% purity by HPLC (MaxPlot detection between 230and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ10.61 (s, 1H), 9.95 (s, 1H), 8.02 (d, J=8.3Hz, 2H), 7.96 (d, J=8.3 Hz, 2H), 7.93 (s, 4H).

c) Preparation of4-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzoyl)amino]benzoicacid

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added4-{[4-(hydrazinocarbonyl)benzoyl]amino}benzoic acid. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 126 mg of the title compound(75%) as a orange solid in 83.3% purity by HPLC (R_(t): 3.78, gradientof 8 min. MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.88 (br s, 1H), 12.64 (br s, 1H), 11.49(s, 1H), 10.73 (s, 1H), 8.14-7.85 (m, 9H), 7.73 (d, J=7.1 Hz, 1H), 6.82(d, J=7.1 Hz, 1H).

M⁻(ESI (LC/MS)⁻): 553; M⁺(ESI (LC/MS)⁺): 555.

Example 693-(3,4-Dihydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamidea) Preparation of methyl4-{[3-(3,4-dihydroxyphenyl)propanoyl]amino}benzoate (Compound C ofScheme 2)

To a solution of 3,4-dihydroxyhydrocinnamic acid (723 mg, 3.97 mmol) inanhydrous THF (20 mL) were added N-methylmorpholine (0.44 mL, 3.97 mmol)and isobutylchloroformate (0.52 mL,3.97 mmol) at 0° C. After 45 min, at0° C., a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) inanhydrous THF (4 mL) was added to the reaction mixture. After 5 min thetemperature was allowed to warm up to rt and stir overnight. Afterextraction with EtOAc (100 mL), washing with HCl (0.1N, 50 mL) and asaturated aqueous solution of NaHCO₃ (50 mL), the organic layer wasdryed over sodium sulfate and evaporated under vacuo to give a yellowoil. Purification by flash chromatography using DCM/MeOH (95/5) aseluant gave the title compound as a colourless oil (22%) in a 94.8%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.21 (s, 1H), 8.68 (s, 2H), 7.89 (d, J=8.8Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 6.61 (m, 2H), 6.46 (dd, J=8.0, 1.8 Hz,1H), 3.80 (s, 3H), 2.72 (t, J=7.4 Hz, 2H), 2.56 (t, J=7.4 Hz, 2H).

b) Preparation of3-(3,4-dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide(Scheme 2, compound B)

To a suspension of methyl4-{[3-(3,4-dihydroxyphenyl)propanoyl]amino}benzoate (227 mg, 0.72 mmol)in EtOH (3.5 mL) was added hydrazine hydrate (0.55 mL). After stirringfor 15 h at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out. Filtration, washing with EtOH (2×1 mL) and water(3×1 mL) and drying under vacuo at 70° C. for 2 hrs gave 117 mg of thetitle compound (52%) as a white solid in 99.6% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.07 (s, 1H), 9.61 (s, 1H), 8.65 (s, 4H),7.75 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 6.60 (m, 2H), 6.46 (dd,J=7.9, 1.5 Hz, 1H), 4.41 (s, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.54 (t, J=7.5Hz, 2H).

c) Preparation of3-(3,4-Dihydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added3-(3,4-dihydroxyphenyl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide.After stirring at 100° C. the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 161 mg ofthe title compound (87%) as a yellow solid in 96% purity by HPLC (R_(t):3.56, gradient of 8 min, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.28 (s, 1H),8.74 (s, 0.4H), 8.73 (s, 0.6H), 8.64 (s, 0.4H), 8.63 (s, 0.6H), 7.82 (m,5H), 7.71 (dd, J=8.3, 1.5 Hz, 1H), 6.81 (d, J=8.3 Hz, 1H), 6.61 (m, 2H),6.47 (d, J=7.9 Hz, 1H), 2.74 (t, J=7.4 Hz, 2H), 2.58 (t, J=7.4 Hz, 2H).

M⁻(ESI (LC/MS)⁻): 569.

Example 703-(3-Hydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamidea) Preparation of methyl 4-{[3-(3-hydroxyphenyl)propanoyl]amino}benzoate(Compound C of Scheme 2)

To a solution of 3-(3-hydroxyphenyl)-propionic acid (198 mg, 1.19 mmol)in anhydrous THF (5 mL) were added N-methylmorpholine (1.2 equiv.) andisobutylchloroformate (1.2 equiv.) at 0° C. After 30 min, at 0° C., asolution of methyl 4-aminobenzoate (150 mg, 0.99 mmol) in anhydrous THF(1 mL) was added to the reaction mixture. After 5 min the temperaturewas allowed to warm up to rt and stir overnight. After extraction withEtOAc (100 mL), washing with HCl (0.1N, 50 mL) and a saturated aqueoussolution of NaHCO₃ (50 mL), the organic layer was dryed over sodiumsulfate and evaporated under vacuo to give a yellow oil. Purification byflash chromatography using EtOAc/cyclohexane as eluant andrecrystallization from DCM/MeOH/TEA (10/0.4/0.1) gave the title compoundas a white solid (32%) in 98.9% purity by HPLC (MaxPlot detectionbetween 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.24 (s, 1H), 9.25 (s, 1H), 7.89 (d, J=8.6Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.05 (m, 1H), 6.64 (m, 2H), 6.56 (m,1H), 3.80 (s, 3H), 2.81 (m, 2H), 2.61 (m, 2H).

b) Preparation ofN-[4-hydrazinocarbonyl)phenyl]-3-(3-hydroxyphenyl)propanamide Compound Cof Scheme 2)

To a suspension of methyl4-{[3-(3-hydroxyphenyl)propanoyl]amino}benzoate (95 mg, 0.32 mmol) inEtOH (3 mL) was added hydrazine hydrate (0.9 mL). After stirring for 21hrs at reflux, the reaction mixture was cooled to rt and a white solidprecipitated out. Filtration, washing with water (3×1 mL), and dryingunder vacuo at 70° C. for 1 hr gave 46 mg of the title compound (480%)as a white solid in 91% purity by HPLC (MaxPlot detection between 230and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.09 (s, 1H), 9.61 (s, 1H), 9.25 (s, 1H),7.75 (d, J=7.8 Hz, 2H), 7.62 (d, J=7.8 Hz, 2H), 7.05 (m, 1H), 6.59 (m,3H), 4.40 (s, 2H), 2.81 (m, 2H), 2.59 (m, 2H).

c) Preparation of3-(3-Hydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide

Into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]-3-(3-hydroxyphenyl)propanamide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 45 mg of the titlecompound (63%) as a yellow solid in 92.4% purity by HPLC (R_(t): 3.88,gradient of 8 min, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.31 (s, 1H),9.26 (s, 1H), 7.82 (m, 5H), 7.71 (d, J=7.9 Hz, 1H), 7.06 (m, 1H), 6.81(d, J=7.9 Hz, 1H), 6.65 (m, 2H), 6.57 (d, J=8.3 Hz, 1H), 2.83 (t, J=7.1Hz, 2H), 2.64 (t, J=7.1 Hz, 2H).

M⁻(ESI (LC/MS)⁻): 553; M⁺(ESI (LC/MS)⁺): 555.

Example 714-Nitro-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3-dione in acetic acid was added4-nitrobenzohydrazide. After stirring at 100° C. the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 165 mg of the title compound (85%) as a orange solid in95.3% purity by HPLC (R_(t): 4.80, 5.53, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 341° C. (decomp).

M⁺(APCI⁺): 389.

Example 72 Methyl4-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3-dione in acetic acid was added methyl4(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 86 mg of the title compound (80%) as a orangepowder in 94% purity by HPLC (R_(t): 4.17, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M⁻(APCI⁻): 432.

Example 734-Methoxy-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3-dione in acetic acid was added4-methoxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 53 mg of the title compound (57%) as a orange powder in93% purity by HPLC (R_(t): 4.11, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M⁻(APCI⁻): 374; M⁺(APCI⁺): 376.

Example 74N-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-3-phenylpropanamidea) Preparation of methyl 4-[(3-phenylpropanoyl)amino]benzoate (CompoundC of Scheme 2)

To a solution of methyl 4-aminobenzoate (825 mg, 5.46 mmol) in anydrouspyridine (16 mL) was added dropwise hydrocinnamoyl chloride (990 μL) at0° C. After 5 min the temperature was allowed to warm up to rt. After 90min aminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 1200mg) was added and the resulting mixture was stirred overnight at rt.After rinsing the resin and filtration, water (200 mL) was added to thefiltrate and a white solid precipated out. Filtration and washing withwater gave a solid which was dried under vacuo at 60° C. overnight. Thetitle compound (1.40 g) was obtained as a white solid (90%) in 98.2%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H), 7.89 (d, J=8.9 Hz, 2H), 7.71(d, J=8.9 Hz, 2H), 7.26 (m, 4H), 7.17 (m, 1H), 3.80 (s, 3H), 2.91 (t,J=7.6 Hz, 2H), 2.66 (t, J=7.6 Hz, 2H).

M⁻(APCI⁻): 282.

b) Preparation of N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide(Scheme 2, compound B)

To a suspension of methyl 4-[(3-phenylpropanoyl)amino]benzoate (1.40 g,4.94 mmol) in EtOH (16 mL) was added hydrazine hydrate (3.6 mL). Afterstirring for 16 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with water (4×5 mL)and drying under vacuo at 60° C. for 2 hrs gave 1.08 g of the titlecompound (77%) as a white solid in 99.1% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.06 (s, 1H), 9.56 (s, 1H), 7.71 (d,J.=8.7Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), 7.21 (m, 4H), 7.12 (m, 1H), 4.37(s, 2H), 2.85 (t, J=7.7 Hz, 2H), 2.59 (t, J=7.7 Hz, 2H).

c) Preparation ofN-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)-3-phenylpropanamide

Into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid wasadded N-[4-(hydrazinocarbonyl)phenyl]-3-phenylpropanamide. Afterstirring at 100° C. the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 621 mg of the titlecompound (79%) as a yellow powder in 99.3% purity by HPLC (R_(t): 4.33,gradient of 8 mm, MaxPlot detection between 230 and 400 nm).

M.p. 326° C.

IR (neat) v 3181, 1667, 1595, 1497, 1251, 1149, 1120, 917, 756 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 11.48 (s, 1H), 10.32 (s, 1H),7.85 (d, J=9.1 Hz, 2H), 7.79 (d, J=9.1 Hz, 2H), 7.69 (d, J=2.1 Hz, 1H),7.56 (dd, J=8.3, 2.1 Hz, 1H), 7.27 (m, 4H), 7.18 (m, 1H), 6.93 (d, J=8.3Hz, 1H), 2.92 (t, J=7.7 Hz, 2H), 2.68 (t, J=7.7 Hz, 2H).

M⁻(APCI⁻): 491.

Example 75N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-{3-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzohydrazide

A suspension of 5-bromo-1H-indole-2,3-dione (67 mg, 0.30 mmol and) and4-(3-hydrazino-3-oxopropyl)benzohydrazide (0.03 mg, 0.13 mmol) in aceticacid (2 mL) was heated at 100° C. for 80 min. The reaction mixture wascooled to rt and a yellow solid precipitated out. Filtration, washingwith AcOH (3×1 mL) and with AcOH/water (2×1 mL) and water (3×1 mL) anddrying in vacuo at 70° C. for 4 hrs gave 68 mg of the title compound ina 79% yield as a yellow solid.

M⁻(APCI⁻): 637.

Example 76N-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-phenoxyacetamidea) Preparation of N-[4-hydrazinocarbonyl)phenyl]-2-phenoxyacetamide(Scheme 2, compound B)

To a suspension of methyl 4-[(phenoxyacetyl)amino]benzoate (843 mg, 2.95mmol) in EtOH (10 mL) was added hydrazine hydrate (2.15 mL). Afterstirring for 15 hrs at reflux, the reaction mixture was cooled to rt.Water (10 mL) was added to the reaction mixture and a white solidprecipitated out. Filtration, washing with EtOH/water (2×2 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 6 hrs gave 389 mg of thetitle compound (46%) as a white solid in 95.4% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.28 (s, 1H), 9.65 (s, 1H), 7.79 (d, J=8.3Hz, 2H), 7.69 (d, 8.3 Hz, 2H), 7.31 (m, 2H), 6.98 (m, 3H), 4.71 (s, 2H),4.42 (s, 2H).

b) Preparation ofN-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-phenoxyacetamide

Following the general method as outlined in Example 1, into a suspensionof5-bromo-1H-indole-2,3-dione in acetic acid was addedN-[4-(hydrazinocarbonyl)phenyl]-2-phenoxyacetamide. After stirring at100° C. the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 2.4 mg of the title compound(2%) as a yellow powder in 86.4% purity by HPLC (R_(t): 4.41, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 493; M⁺(ESI (LC/MS)⁺): 495.

Example 77N-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzyl)-3-nitrobenzamidea) Preparation of methyl 4-{[(3-nitrobenzoyl)amino]methyl}benzoate(Compound C of Scheme 2)

Under an inert atmosphere, to a stirred solution of methyl4-(aminomethyl)benzoate (50 g, 0.436 mol) and TEA (210 mL, 1.5 mol) inanhydrous DCM (1.0 L) was added a solution of freshly prepared 3-nitrobenzoyl chloride (0.59 mol) in DCM (250 mL). The resulting mixture wasallowed to stir for 2 hrs. The reaction was quenched with a 10% aqueoussolution of sodium hydrogenocarbonate. The organic layer was washed witha 1.5N HCl solution and water. After drying over MgSO₄ and evaporationof the solvent in vacuo, a solid was obtained and purified by flashchromatography to give the title compound (50 g) in a 52% yield as awhite powder.

¹H NMR (300 MHz, DMSO-d₆) δ 9.51 (t, J=5.7 Hz, 1H), 8.73 (t, J=1.9 Hz,1H), 8.41 (ddd, J=8.3, 2.0, 0.7 Hz, 1H), 8.34 (d, J=7.9 Hz, 1H), 7.93(d, J=8.3 Hz, 2H), 7.79 (t, J=8.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 2H), 4.59(d, J=5.7Hz, 2H), 3.83 (s, 3H).

b) Preparation of N-[4-(hydrazinocarbonyl)benzyl]-3-nitrobenzamide(Scheme 2, compound B)

To a suspension of 4-{[(3-nitrobenzoyl)amino]methyl}benzoate (500 mg,1.59 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.16 mL). Afterstirring for 15 h at reflux, the reaction mixture was cooled to rt and awhite solid precipitated out. Filtration, washing with EtOH (2×2 mL),EtOH/water (2×2 mL)and water (2×2 mL), and drying under vacuo at 70° C.for 5 hrs gave 379 mg of the title compound (76%) as a pale yellow solidin 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 9.71 (s, 1H), 9.47 (t, J=5.7 Hz, 1H), 8.73(s, 1H), 8.40 (d, J=8.3 Hz, 1H), 8.33 (d, J=7.5 Hz, 1H), 7.79 (m, 3H),7.39 (d, J=8.3 Hz, 2H), 4.55 (d, J=5.7 Hz, 2H), 4.45 (s, 2H).

c) Preparation ofN-(4-{[2-5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzyl)-3-nitrobenzamide

Into a suspension of 5-bromo-1H-indole-2,3-dione in acetic acid wasadded N-[4-(hydrazinocarbonyl)benzyl]-3-nitrobenzamide. After stirringat 100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 95 mg of the title compound(69%) as a orange powder in 88.9% purity by HPLC (R_(t): 4.14, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 522; M⁺(ESI (LC/MS)⁺): 524.

Example 78 Methyl3-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoatea) Preparation of methyl 3-(2-hydrazino-2-oxethoxy)benzoate (Compound Cof Scheme 2)

To a suspension of methyl 3-(2-methoxy-2-oxoethoxy)benzoate (887 mg,3.96 mmol) in MEOH (50 mL) was added hydrazine hydrate (1.92 mL). Afterstirring for 0.5 h at rt, water (50 mL) was added and the reactionmixture was filtered. Washing with water (3×5 mL) and drying under vacuoat 70° C. overnight gave 713 mg of the title compound (80%) as a whitesolid in 98.3% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 9.38 (s, 1H), 7.56 (d, J=7.5 Hz, 1H), 7.50(br s, 1H), 7.44 (dd, J=8.3, 7.5 Hz, 1H), 7.24 (dd, J=8.3, 1.5 Hz, 1H),4.55 (s, 2H), 4.32 (s, 2H), 3.84 (s, 3H).

b) Preparation of methyl3-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate(Scheme 2, compound B)

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3dione in acetic acid was added methyl3-(2-hydrazino-2-oxoethoxy)benzoate. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 39 mg of the title compound (34%) as a orangepowder in 97.5% purity by HPLC (R_(t): 4.26, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

M⁻(ESI (LC/MS)⁻): 432; M⁺(ESI (LC/MS)⁺): 434.

Example 79N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazidea) Preparation of methyl [4-(2H-tetrazol-5-yl)phenoxy]acetate (CompoundC of Scheme 2)

A solution of methyl (4-F)acetate (70 g, 0.36 mol), TEA.Hcl (125 g, 0.91mol) and NaN3 (60 g, 0.91 mol) in dry toluene (1.5 L) was strirred underreflux for 72 hrs. After cooling to rt, the reaction mixture was quencedwith water (400 mL). After extraction, the aqueous layer was washed withtoluene (2×250 mL). Then the organic layer was treated with a 1.5Nsolution of HCl until pH=2-3. A white solid precipitated out. Dryingunder vacuo gave the hydrochloride salt of the title compound (43 g) ina 50% yield.

¹H NMR (300 MHz, DMSO-d₆) δ 8.1 (d, J=8.6 Hz, 2H), 7.2 (d, J=8.6 Hz,2H), 4.96 (s, 2H), 3.76 (s, 3H).

M⁻(APCI⁻): 233.

b) Preparation of 2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide (Scheme2, compound B)

To a suspension of methyl [4-(2H-tetrazol-5-yl)phenoxy]acetate (1.10 g,4.06 mmol) in MeOH (30 mL) was added hydrazine hydrate (2.0 mL). Afterstirring for 90 min at rt, the reaction mixture was evaporated off. Theresidue was taken up with MeOH (10 mL) and a white solid precipitatedout. Filtration, washing with MeOH (2×3 mL) and drying under vacuo at70° C. for 16 hrs gave 741 mg of the title compound (78%) as a whitesolid in 99.9% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 9.41 (br s, 1H), 7.96 (d, J=8.7 Hz, 2H),7.16 (d, J=8.7 Hz, 2H), 4.58 (s, 2H).

c) Preparation ofN′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3-dione in acetic acid was added2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide. After stirring at 100°C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 40 mg of the title compound(68%) as a orange Solid in 94.9% purity by HPLC (R_(t): 3.34, gradientof 8 mini, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.66 (br s, 0.6H), 12.50 (br s, 0.4H);11.39 (s, 1H), 8.00 (d, J=8.3 Hz, 2H), 7.70 (br s, 1H), 7.56 (dd, J=8.3,1.5 Hz, 1H), 7.26 (d, J=8.3 Hz, 2H), 6.92 (d, J=8.3 Hz, 1H), 5.42 (br s,0.8H), 5.00 (br s, 1.2H).

M⁻(APCI⁻): 442.

Example 80N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(1H-tetrazol-5-yl)benzohydrazidea) Preparation of 4-(1H-tetrazol-5-yl)benzohydrazide (Scheme 2, compoundB)

To a suspension of methyl 4-(1H-tetrazol-5-yl)benzoate (1.00 g, 4.16mmol) in EtOH (15 mL) was added hydrazine hydrate (3.0 mL). Afterstirring for 15 hrs at reflux, the reaction mixture was allowed to warmup to rt. A white solid precipitated out. Filtration, washing with EtOH(2×3 mL), EtOH/water (2×3 mL) and water (2×3 mL) and drying under vacuoat 70° C. for 5 hrs gave 677 mg of the title compound as a white solidin a 80% yield.

¹H NMR (DMSO-d₆, 300 MHz) δ 9.95 (br s, 1H), 8.10 (d, J=8.3 Hz, 2H),8.01 (d, J=8.3 Hz, 2H).

b) Preparation ofN′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(1H-tetrazol-5-yl)benzohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3dione in acetic acid was added4-(1H-tetrazol-5-yl)benzohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 29 mg of the title compound (53%) as a orangeSolid in 89.1% purity by HPLC (R_(t): 3.29, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.89 (s, 1H), 11.52 (s, 1H), 8.26 (d, J=8.3Hz, 2H), 8.10 (d, J=8.3 Hz, 2H), 7.70 (s, 1H), 7.57 (d, J=8.2 Hz, 1H),6.93 (d, J=8.2 Hz, 1H).

M⁻(APCI⁻): 412.

Example 81N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-6-methoxy-5-nitronicotinohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3-dione in acetic acid was added6-methoxy-5-nitronicotinohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 81 mg of the title compound (87%) as a orangesolid in 98.7% purity by HPLC (R_(t): 4.56, gradient of 8 min, MaxPlotdetection between 230 and 400 nm).

20 M.p. 345° C. (decomp).

IR (neat) ν 3164, 1695, 1612, 1439, 1290, 1243, 1202, 1140, 119, 814,762, 726 cm⁻¹.

¹H NMR (DMSO-d₆, 300 MHz) δ 14.61 (s, 1H), 11.39 (s, 1H), 9.16 (d, J=1.9Hz, 1H), 8.86 (d, J=1.9 Hz, 1H), 7.82 (br s, 1H), 7.70 (dd, J=8.1, 1.5Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 3.92 (s, 3H).

M⁻(APCI⁻): 466; M⁺(APCI⁺): 468.

Analysis calculated for C₁₅H₁₀IN₅O₅.H₂O: C,38.73; H,2.68; N,13.28%.Found: C,38.72; H,2.80; N,13.48%.

Example 823-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-sulfonyl}benzoicacid

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added3-(hydrazinosulfonyl)benzoic acid. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 131 mg of the title compound (71%) as a yellowsolid in 87.8% purity by HPLC (R_(t): 4.71, gradient of 10 min, MaxPlotdetection between 230 and 400 nm).

M.p. 233° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 11.23 (s, 1H), 8.47 (s, 1H), 8.23 (m, 2H),7.77 (t, J=7.9 Hz, 1H), 7.65 (m, 2H), 6.72 (d, J=8.7 Hz, 1H).

Example 832-Hydroxy-5-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]sulfonyl}benzoicacid

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added5-(hydrazinosulfonyl)-2-hydroxybenzoic acid. After stirring at 100° C.,the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 108 mg of the title compound (59%) as ayellow solid in 92.8% purity by HPLC (R_(t): 4.85, gradient of 10 min,MaxPlot detection between 230 and 400 mn).

M.p. 240° C. (decomp).

¹H NMR (DMSO-d₆, 300 MHz) δ 12.45 (br s, 1H), 11.25 (s, 1H), 8.33 (d,J=2.4 Hz, 1H), 8.04 (dd, J=8.9,2.4 Hz, 1H), 7.65 (m, 2H), 7.17 (d, J=8.9Hz, 1H), 6.73 (d, J=8.3 Hz, 1H).

Example 84N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-5-(2-pyridinyl)-2-thiophenesulfonohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added5-(2-pyridinyl)-2-thiophenesulfonohydrazide. After stirring at 100° C.,the reaction mixture was cooled to rt and a yellow solid precipitatedout. Filtration on a fritté, washing with AcOH, water and drying undervacuo at 60° C. overnight gave 23 mg of the title compound (23%) as ayellow solid in 94.8% purity by HPLC (R_(t): 3.68, 5.13, gradient of 8min, MaxPlot detection between 230 and 400 nm).

M.p. 162° C. (decomp).

M⁺(APCI⁺): 511.

Example 854-Chloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-nitrobenzenesulfonohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-chloro-3-nitrobenzenesulfonohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH, water and drying under vacuoat 60° C. overnight gave 78 mg of the title compound (77%) as a yellowsolid in 73% purity by HPLC (R_(t): 3.65, 5.39, gradient of 8 min,MaxPlot detection between 230 and 400 nm).

M.p. 219° C. (decomp).

Example 86N-Dodecyl-3-[(4-hydroxybenzoyl)hydrazono]-2-oxo-2,3-dihydro-1H-indole-7-carboxamidea) Preparation of N-dodecyl-2,3-dioxo-7-indolinecarboxamide

Into a solution of 2,3-dioxo-7-indolinecarboxylic acid (1000 mg, 5.23mmol), 1-dodecanamine (1066 mg, 5.75 mmol), TEA (1.60 mL, 11.51 mmol),EDCI.HCl (1102 mg, 5.75 mmol) and HOBt (777 mg, 5.75 mmol) in DMF (60mL). The resulting mixture was allowed to stir at rt for 24 hrs. Thesolvent was evaporated off and the residue was taken up in DCM to bepurified by flash chromatography using DCM/MeOH (98/2) as eluant. Agummy orange solid was collected to be identified as the title compound(44%) in a 96.0% purity by HPLC (MaxPlot detection between 230 and 400nm).

M⁻(APCI⁻): 357; M⁺(APCI⁺): 359.

b) Preparation ofN-dodecyl-3-[(4-hydroxybenzovyl)hydrazono]-2-oxo-2,3-dihydro-1H-indole-7-carboxamide

Following the general method as outlined in Example 1, into a suspensionof N-dodecyl-2,3-dioxo-7-indolinecarboxamide in acetic acid was added4-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 46 mg of the title compound (33%) as a yellow powder in99.8% purity by HPLC (R_(t): 5.95, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M⁻(ESI⁻): 491.

Example 87 Methyl{3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate

Into a solution of4-hydroxy-N-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide(200 mg, 0.49 mmol) in anhydrous DMF (4 mL) were added DBU (0.11 mL,0.73 mmol) and methyl bromoacetate (0.95 mL, 0.98 mmol). The resultingmixture was stirred at rt for 1 hr and quenched with water. Uponaddition of 1N HCl a yellow solid precipitated out. Filtration andwashing with water gave a yellow solid which was recrystallized fromAcOH to give the title compound as a yellow powder (79 mg, 34%) in 97.0%purity by HPLC (MaxPlot detection between 230 and 400 nm).

Example 88N-Dodecyl-3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indole-1-carboxamidea) Preparation of N-dodecyl-2,3-dioxo-7-indolinecarboxamide

Into a solution of 2,3-dioxo-7-indolinecarboxylic acid (1000 mg, 5.23mmol), 1-dodecanamine (1066 mg, 5.75 mmol), TEA (1.60 mL, 11.51 mmol),EDCI.HCl (1102 mg, 5.75 mmol) and HOBt (777 mg, 5.75 mmol) in DMF (60mL). The resulting mixture was allowed to stir at rt for 24 hrs. Thesolvent was evaporated off and the residue was taken up in DCM to bepurified by flash chromatography using DCM/MeOH (98/2) as eluant. Agummy orange solid was collected to be identified as the title compound(44%) in a 96.0% purity by HPLC (MaxPlot detection between 230 and 400nm).

M⁻(APCI⁻): 357; M⁺(APCI⁺): 359.

b) Preparation ofN-Dodecyl-3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indole-1-carboxamide

Following the general method as outlined in Example 1, into a suspensionof N-dodecyl-2,3-dioxo-7-indolinecarboxamide in acetic acid was added4-hydroxybenzohydrazide. After stirring at 100° C., the reaction mixturewas cooled to rt and a yellow solid precipitated out. Filtration on afritté, washing with AcOH, water and drying under vacuo at 60° C.overnight gave 26 mg of the title compound (68%) as a yellow powder in96.3% purity by HPLC (R_(t): 7.25, gradient of 8 min, MaxPlot detectionbetween 230 and 400 nm).

M⁻(APCI⁻): 617; M⁺(APCI⁺): 619.

Example 89 Methyl(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetatea) Preparation of methyl 4-(hexanoylamino)benzoate (Compound C of Scheme2)

To a solution of methyl 4-aminobenzoate (500 mg, 3.31 mmol) in anhydrouspyridine (10 mL) was added dropwise hexanoyl chloride (550 μL) at 0° C.After 5 min the temperature was allowed to warm up to rt. After 90 minaminomethyl resin (Polymers Laboratories PL-AMS, 1.93 mmol/g, 720 mg)was added and the resulting mixture was stirred overnight at rt. Afterfiltration and rinsing the resin, water (125 mL) was added to thefiltrate and a white solid precipated out. Filtration and washing withwater gave a solid which was dried under vacuo at 60° C. overnight. Thetitle compound (699 mg) was obtained as a white solid (85%) in 96.9%purity by HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.20 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.72(d, J=8.7 Hz, 2H), 3.80 (s, 3H), 2.32 (t, J=7.4 Hz, 2H), 1.58 (m, 2H),1.28 (m, 4H), 0.86 (t, J=6.8 Hz, 3H).

M⁻(APCI⁻): 248.

b) Preparation of N-[4(hydrazinocarbonyl)phenyl]hexanamide (Scheme 2,Compound B)

To a suspension of methyl 4-(hexanoylamino)benzoate (583 mg, 2.34 mmol)in ETOH (8 mL) was added hydrazine hydrate (1.8 mL). After stirring for15 h at reflux, the reaction mixture was cooled to rt and a white solidprecipitated out. Filtration, washing with water (2×2 mL), and dryingunder vacuo at rt for 72 hrs gave 321 mg of the title compound (55%) asa white solid in 96.6% purity by HPLC (MaxPlot detection between 230 and400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.06 (s, 1H), 9.60 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 4.42 (s, 2H), 2.30 (t, J=7.2 Hz, 2H),1.58 (m, 2H), 1.28 (m, 4H), 0.86 (m, 3H).

c) Preparation of Methyl(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate

Following the general method as outlined in Example 1, into a suspensionof methyl (5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate in aceticacid was added N-[4-(hydrazinocarbonyl)phenyl]hexamide. After stirringat 100° C., the reaction mixture was cooled to rt and a yellow solidprecipitated out. Filtration on a fritté, washing with AcOH, water anddrying under vacuo at 60° C. overnight gave 183 mg of the title compound(91%) as a yellow powder in 99.4% purity by HPLC (R_(t): 4.97, gradientof 8 min, MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) 8 13.56 (s, 1H), 10.28 (s, 1H), 7.91 (d, J=1.5Hz, 1H), 7.83 (m, 5H), 7.11 (d, J=8.6 Hz, 1H), 4.74 (s, 2H), 3.70 (s,3H), 2.34 (t, J=7.4 Hz, 2H), 1.60 (m, 2H), 1.29 (m, 4H), 0.87 (t, J=6.8Hz, 3H).

M⁻(APCI⁻): 575; M⁺(APCI⁺): 577.

Example 90(3-{[4-(Hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3dihydro-1H-indol-1-yl)aceticacid

Into a suspension of methyl(3-{([4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate(650 mg, 1.13 mmol) in THF/H₂O (2/1) (25 mL) was added NaOH (1.0 N, 5.6mL). The resulting solution was stirred at rt for 0.5 hr and quenchedwith HCl (5 N, 5 mL) and water (25 mL). A yellow solid precipitated out.Filtration, washing with water (4×10 mL) and drying under vacuo at 60°C. for 15 hrs gave a yellow solid. Recrystallization from AcOH (60 mL)gave the title compound as a yellow powder (411 mg, 64%) in 99.9% purityby HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 298° C. (decomp).

¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 13.36 (s, 1H), 10.29 (s, 1H),7.85 (m, 6H), 7.10 (d, J=8.3 Hz, 1H), 4.61 (s, 2H), 2.34 (t, J=7.4 Hz,2H), 1.59 (m, 2H), 1.29 (m, 4H), 0.87 (m, 3H).

M⁺(APCI⁺): 563.

Example 91(3-{[4-(Hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)aceticacid, tromethanine (2-amino-2-hydroxymethyl-1,3-propanediol) salt

A solution of(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)aceticacid (22 mg, 0.039 mmol) and tris(hydroxymethyl)amino methane (4.8 mg, 1equiv.) in MeOH/H₂O (4/1) (25 mL) was stirred for 15 min. The solventwas partially evaporated off under vacuo. Then the solution waslyophilized to give the title compound as a yellow solid (19 mg, 71%) in98.7% purity by HPLC (detection at 254 nm).

M.p. 207-210° C. (decomp).

Example 92(3-{[4-(Hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)aceticacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (135 mg, 0.69 mmol) in MeOH (50mL) at reflux was added a solution of(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)aceticacid (353 mg, 0.63 mmol) in warm DMSO (5 mL). After 10 min of stirring,the heating bath was removed and Et₂O (250 mL) was added. A yellow solidprecipitated out. Filtration, washing with Et₂O (10×10 mL) and dryingunder vacuo at 60° C. for 24 hrs gave a title compound as a yellow solid(421 mg, 88%) in 99.7% purity by HPLC (MaxPlot detection between 230 and400 nin).

M.p. 165-167° C. (decomp).

Example 932-(4-Cyanophenoxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazidea) Preparation of 2-(4cyanophenoxy)acetohydrazide (Scheme 2, compound B)

To a solution of methyl (4-cyanophenoxy)acetate (3.52 g, 18.4 mmol) inMEOH (100 mL) was added hydrazine hydrate (8.9 mL). After stirring for 1h at rt, a solid precipitated out. Filtration, washing with MeOH (5 mL)and water (4×10 mL) and drying under vacuo at 50° C. overnight gave thetitle compound (2.63 g, 75%) as a white solid in 98.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.77 (d, J=8.7 Hz, 2H), 7.10(d, J=8.7 Hz, 2H), 4.59 (s, 2H), 4.33 (s, 2H).

b) Preparation of2-(4-cyanophenoxy)-N-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3dione in acetic acid was added2-(4-cyanophenoxy)acetohydrazide. After stirring at 100° C., thereaction mixture was cooled to rt and a yellow solid precipitated out.Filtration on a fritté, washing with AcOH and water, drying under vacuoat 50° C. overnight and recrystallization from DMSO gave the titlecompound (642 mg, 60%) as an orange solid in 99.3% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 330° C. (decomp).

IR (neat) ν 3174, 3067, 2224, 1693, 1501, 1206, 1171, 1136, 825 cm⁻¹.

¹H NMR (300 MHz, DMSO-d₆) δ 13.57 (br s, 0.5H), 12.45 (br s, 0.5H),11.36 (s, 1H), 7.82 (m, 3H), 7.71 (dd, J=8.1, 1.7 Hz, 1H), 7.20 (d,J=8.3 Hz, 2H), 6.79 (d, J=8.1 Hz, 1H), 5.44 (br s, 1H), 5.02 (br s, 1H).

M⁻(APCI⁻): 445.

Analysis calculated for C₁₇H₁₁IN₄O₃.0.7 H₂O: C,44.50; H,2.72; N,12.21%.Found: C,44.47; H,2.53; N,12.15%.

Example 944-({2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}thio)-3-nitrobenzenesulfonamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid was added4-[(2-hydrazino-2-oxoethyl)thio]-3-nitrobenzenesulfonamide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. overnight gave 24 mg of the titlecompound (61%) as a yellow solid in 99.3% purity by HPLC (R_(t): 3.51,4.17, gradient of 8 rnin, MaxPlot detection between 230 and 400 nm).

M.p. 282° C. (decomp).

M⁻(ESI (LC/MS)⁻): 560; M⁺(ESI (LC/MS)⁺): 562.

Example 95N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-N-methyl-3-phenylpropanamidea) Preparation of methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate(Compound C of Scheme 2)

To a solution of methyl 4-methylaminobenzoate (1.0 g, 6.05 mmol) inanhydrous pyridine (20 mL) was added dropwise hydrocinnamoyl chloride(1080 μL) at rt. After 16 hrs water (5 mL) was added and the resultingmixture was stirred for 1 hr at rt. The resulting mixture was pouredinto water (300 mL) and HCl (5 N, 50 mL) was added. The compound wasextracted with AcOEt (2×300 mL) and washed with a saturated aqueoussolution of NaHCO₃ (150 mL). The combined organic layers were dried overMgSO₄ and evaporated under vacuo to give the title compound (1.80 g) wasobtained as a beige solid (95%) in 95.3% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 7.96 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz,2H), 7.24-7.07 (m, 5H), 3.84 (s, 3H), 3.19 (s, 3H), 2.78 (t, J=7.6 Hz,2M), 2.42 (m, 2H).

b) Preparation ofN-[4-(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide (Scheme 2,compound B)

To a solution of methyl 4-[methyl(3-phenylpropanoyl)amino]benzoate (1600mg, 5.38 mmol) in EtOH (14 mL) was added hydrazine hydrate (4.0 mL). Theresulting mixture was stirred for 16 h at reflux and evaporated undervacuo to give the title compound (1600 mg, 100%) as a gummy colorlessoil, which was used in the next step without any further purification.

¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (s, 1H), 7.82 (d, J=8.5 Hz, 2H), 7.30(d, J=8.5 Hz, 2H), 7.24-7.06 (m, 5H), 4.51 (br s, 2H), 3.16 (s, 3H),2.77 (t, J=7.7 Hz, 2H), 2.36 (m, 2H).

c) Preparation ofN-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-N-methyl-3-phenylpropanamide

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3dione in acetic acid was addedN-[4(hydrazinocarbonyl)phenyl]-N-methyl-3-phenylpropanamide. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH andwater and drying under vacuo at 60° C. overnight gave the title compound(226 mg, 56%) as an orange solid in 96.7% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

M.p. 239° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 11.48 (s, 1H), 7.80 (m, 3H),7.82 (s, 1H), 7.45 (m, 2H), 7.15 (m, 5H), 6.80 (m, 1H), 3.29 (s, 3H),2.81 (m, 2H), 2.49 (m, 2H).

M⁻(APCI⁻): 551. M⁺(APCI⁺): 553.

Example 96 Methyl{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetatea) Preparation of methyl(5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate (Precursor ofCompound A)

Into a solution of 5-iodo-1H-indole-2,3dione (10.0 g, 36.6 mmol) inanhydrous DMF (180 ml) were added DBU (8.2 mL, 54.9 mmol) and methylbromoacetate (5.1 mL, 54.9 mmol). After stirring at rt for 45 min, thereaction mixture was quenched with water (600 mL) and HCl (1N, 100 mL).Extraction with EtOAc (3×500 mL), drying over MgSO₄ and evaporationunder vacuo gave a residue. Recrystallization from AcOEt 150 mL) gavethe title compound as an orange powder (6.45 g, 51%) in 99.1% purity byHPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 8.01 (dd, J=8.2, 1.8 Hz, 1H), 7.87 (d, J=1.8Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 4.61 (s, 2H), 3.69 (s, 3H).

b) Preparation of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (Compound C ofScheme 2)

To a solution of 3-(3,4-methylenedioxyphenyl)-propionic acid (501 mg,2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C.After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg,2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture.After 30 min the temperature was allowed to warm up to rt and stir for24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1 N,50 mL) and a saturated aqueous solution of NaHCO₃ (50 mL), the organiclayer was dried over sodium sulfate and evaporated under vacuo to give asolid. The residue was taken up in Et₂O, filtrated and washed with Et₂Ogave the title compound as a white solid (62%) in 99.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.22 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.70(d, J=8.7 Hz, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.68(dd, J=7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 3.80 (s, 3H), 2.82 (t, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H).

c) Preparation of3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide(Scheme 2, compound B)

To a suspension of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol)in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirringfor 15 hrs at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out. Filtration, washing with EtOH (2×1 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of thetitle compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.60 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 6.82 (d, J=1.5 Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.68 (dd, J=7.9, 1.5 Hz, 1H), 5.94 (s, 2H), 4.41 (s, 2H), 2.82(t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H).

d) Preparation of methyl{3-[(4-{[3-1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate

Following the general method as outlined in Example 1, into a suspensionof methyl (5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)acetate in aceticacid was added3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 519 mg ofthe title compound (95%) as a yellow powder in 98.6% purity by HPLC(R_(t): 4.44, 4.94 gradient of 8 min, MaxPlot detection between 230 and400 nm).

M.p. 236° C.

¹H NMR (DMSO-d₆, 300 MHz) δ 13.56 (s, 1H), 10.30 (s, 1H), 7.91-7.78 (m,6H), 7.11 (d, J=8.3 Hz, 1H), 6.81 (m, 2H), 6.70 (d, J=7.9 Hz, 1H), 5.95(s, 2H), 4.74 (s, 2H), 3.70 (s, 3H), 2.84 (t, J=7.4 Hz, 2H), 2.63 (t,J=7.4 Hz, 2H).

M⁻(ESI (LC/MS)⁻): 653; M⁺(ESI (LC/MS)⁺): 655.

Example 97 Methyl4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-4-oxobutanoatea) Preparation of tert-butyl2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate(Compound B of Scheme 2)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (500mg, 1.99 mmol) in anhydrous pyridine (10 mL) was added dropwise3-carbomethoxypropionyl chloride (Fluka) (300 μL) at rt. After 60 min,aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 400 mg)was added and the resulting mixture was stirred overnight at rt. Afterfiltration and rinsing the resin, water (80 mL) was added into thefiltrate and a white solid precipitated out. Filtration and washing withwater gave a white solid, which was dried under vacuo at 70° C. for 2hrs. The title compound (461 mg) was obtained as a white solid (63%) in96.0% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 111-113° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s, 1H), 10.05 (s, 1H), 8.84 (s, 1H),7.80 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 3.59 (s, 3H), 2.62 (m,4H), 1.42 (s, 9H).

M⁻(ESI (LC/MS)⁻): 364; M⁺(ESI (LC/MS)⁺): 366.

b) Preparation of methyl4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-4-oxobutanoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-{4-[(4-methoxy-4-oxobutanoyl)amino]benzoyl}hydrazinecarboxylate. Afterstirring at 100° C., the reaction mixture was cooled to rt and an orangesolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 60° C. for 60 min gave 89 mg of the titlecompound (92%) as an orange solid in 98.8% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

M.p. 291° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.41 (s, 1H),7.85 (m, 3H), 7.79 (d, J=8.7 Hz, 2H), 7.71 (dd, J=8.3, 1.8 Hz, 1H), 6.81(d, J=8.3 Hz, 1H), 3.59 (s, 3H), 2.64 (m, 4H).

M⁻(APCI⁻): 519. M⁺(APCI⁺): 521.

Example 983-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamidea) Preparation of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (Compound C ofScheme 2)

To a solution of 3-(3,4-methylenedioxyphenyl)-propionic acid (501 mg,2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C.After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg,2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture.After 30 min the temperature was allowed to warm up to rt and stir for24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1N, 50mL) and a saturated aqueous solution of NaHCO₃ (50 mL), the organiclayer was dryed over sodium sulfate and evaporated under vacuo to give asolid. The residue was taken up in Et₂O, filtrated and washed with Et₂Ogave the title compound as a white solid (62%) in 99.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.22 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.70(d, J=8.7 Hz, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.68(dd, J=7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 3.80 (s, 3H), 2.82 (t, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H).

b) Preparation of3-(1,3-benzodioxol-5-yl)-N-[4-hydrazinocarbonyl)phenyl]propanamide(Scheme 2, compound B)

To a suspension of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol)in ETOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirringfor 15 hrs at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out. Filtration, washing with EtOH (2×1 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of thetitle compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.08 (s, 1H), 9.60 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 6.82 (d, J=1.5 Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.68 (dd, J=7.9, 1.5 Hz, 1H), 5.94 (s, 2H), 4.41 (s, 2H), 2.82(t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H).

c) Preparation of3-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide

Following the general method as outlined in Example 1, into a suspensionof 5-bromo-1H-indole-2,3dione in acetic acid was added3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 151 mg ofthe title compound (89%) as a yellow solid in 98.2% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 325° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.83 (s, 1H), 11.48 (s, 1H), 10.30 (s, 1H),7.86 (d, J=8.7 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.70 (d, J=1.7 Hz, 1H),7.56 (dd, J=8.3, 1.7 Hz, 1H), 6.93 (d, J=8.3 Hz, 1H), 6.81 (m, 2H), 6.70(d, J=7.5 Hz, 1H), 5.95 (s, 2H), 2.84 (t, J=7.3 Hz, 2H), 2.63 (t, J=7.3Hz, 2H).

M⁻(ESI (LC/MS)): 535; M⁺(ESI (LC/MS)⁺): 537.

Example 99{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}aceticacid

Into a suspension of methyl{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate (419 mg, 0.64 mmol) in THF/H₂O (10/1) (200 mL) was added NaOH (1N, 2 mL). The resulting solution was stirred at rt for 1 hr and quenchedwith HCl (5 N, 5 mL) and water (300 mL). A yellow solid precipitatedout. Filtration, washing with water (3×10 mL) and drying under vacuo at70° C. for 15 hrs gave the title compound as a yellow solid (264 mg,64%) in 99.6% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 297° C. (decomp).

¹H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 13.35 (s, 1H), 10.31 (s, 1H),7.85 (m, 6H), 7.11 (m, 1H), 6.83 (m, 2H), 6.71 (m, 1H), 5.94 (s, 2H),4.61 (s, 2H), 2.83 (m, 2H), 2.64 (m, 2H).

M⁻(ESI (LC/MS)⁻): 639; M⁺(ESI (LC/MS)⁺): 641.

Example 100{3-[(4-{[3-(1,3-Benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}aceticacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

The same procedure as employed in the preparation of Example 92 butusing {3-[(4-{[(3-(1,3-benzodioxol-5-yl)propanoyl]aminobenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetic acidgave the title compound (179 mg, 80%) as a yellow solid in 99.9% purityby HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 140-145° C. (decomp).

Example 101 Methyl6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-6-oxohexanoatea) Preparation of tert-butyl2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate(Compound B of Scheme 2)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl6-chloro-6-oxohexanoate (Fluka) (750 μL) at rt. After 30 min,aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 970 mg)was added and the resulting mixture was stirred overnight at rt. Afterfiltration and rinsing the resin, water (160 mL) was added into thefiltrate and a white solid precipitated out. Filtration and washing withwater gave a white solid, which was dried under vacuo at 50° C. for 5hrs. The title compound (981 mg) was obtained as a white solid (63%) in99.8% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 163° C.

¹H NMR (300 MHz, DMSO-d₆) δ 10.13 (s, 1H), 10.05 (s, 1H), 8.84 (s, 1H),7.81 (d, J=8.5 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 357 (s, 3H), 2.34 (m,4H), 1.58 (m, 4H), 1.14 (s, 9H).

M⁻(ESI (LC/MS)⁻): 392; M⁺(ESI (LC/MS)⁺): 394.

b) Preparation of methyl6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-6-oxohexanoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl)hydrazinecarboxylate. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 70° C. for 15 hrs gave 496 mg of the titlecompound (82%) as a yellow solid in 99.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

M.p. 277° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 11.46 (s, 1H), 10.29 (s, 1H),7.82 (m, 5H), 7.71 (d, J=7.9 Hz, 1H), 6.81 (d, J=7.9 Hz, 1H), 3.58 (s,3H), 2.35 (m, 4H), 1.58 (m, 4H).

M⁻(APCI⁻): 547. M⁺(APCI⁺): 549.

Example 102 Methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazino]carbonyl}phenyl)amino]carbonyl}benzoatea) Preparation of tert-butyl2-(4-{[4-(methoxycarbonyl)benzoyl]amino}benzoyl)hydrazinecarboxylate(Compound B of Scheme 2)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl4-(chlorocarbonyl)benzoate (TCI) (948 mg, 4.78 mmol) at rt. After 50min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 960mg) was added and the resulting mixture was stirred for 22 hrs at rtAfter filtration and rinsing the resin, water (160 mL) was added intothe filtrate and a white solid precipitated out. Filtration and washingwith water gave a white solid, which was dried under vacuo at 60° C. for15 hrs. The title compound (1.41 g) was obtained as a white solid (85%)in 98.7% purity by HPLC (MaxPlot detection between 230 and 400 mn).

¹H NMR (300 MHz, DMSO-d₆) δ 10.66 (s, 1H), 10.12 (s, 1H), 8.87 (s, 1H),8.09 (m, 4H), 7.87 (m, 4H), 3.89 (s, 3H), 1.42 (s, 9H).

M⁻(APCI⁻): 412.

b) Preparation of methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]carbonyl}benzoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl24-{[4-(methoxycarbonyl)benzoyl]amino}benzoyl)hydrazinecarboxylate.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. for 72 hrs gave 636 mg ofthe title compound (97%) as a yellow solid in 95.3% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 361° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.84 (s, 1H), 11.47 (s, 1H), 10.81 (s, 1H),8.05 (s, 4H), 8.02 (d, J=8.66 Hz, 2H), 7.91 (d, J=8.29 Hz, 2H), 7.83 (s,1H), 7.71 (d, J=8.29 Hz, 1H), 6.81 (d, J=8.29 Hz, 1H), 3.90 (s, 3H).

M⁻(APCI⁻): 567. M⁺(APCI⁺): 569.

Example 103 Methyl8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-8-oxooctanoatea) Preparation of tert-butyl2-{4-[(9-methoxy-9-oxononanoyl)amino]benzoyl}hydrazinecarboxylate(Compound B of Scheme 2)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl8-chloro-8-oxo-octanoate (Aldrich) (680 μL, 4.78 mmol) at rt. After 90min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 960mg) was added and the resulting mixture was stirred for 20 hrs at rt.After filtration and rinsing the resin, water (160 mL) was added intothe filtrate and a white solid precipitated out. Filtration and washingwith water gave a white solid, which was dried undervacuo at 70° C. for3 hrs. The title compound (1.11 g) was obtained as a white solid (65%)in 98.7% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 106-109° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 10.11 (s, 1H), 10.04 (s, 1H), 8.83 (s, 1H),7.78 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 3.56 (s, 3H), 2.30 (m,4H), 1.57 (m, 4H), 1.14 (s, 9H), 1.28 (m, 4H).

M⁻(APCI⁻): 420.

b) Preparation of methyl8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-8-oxooctanoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-{4-[(9-methoxy-9-oxononanoyl)amino]benzoyl)hydrazinecarboxylate. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 70° C. for 21 hrs gave 611 mg of the titlecompound (95%) as a yellow solid in 98.1% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

M.p. 268° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.27 (s, 1H),7.81 (m, 5H), 7.69 (d, J=7.9 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 3.56 (s,3H), 2.29 (m, 4H), 1.57 (m, 4H), 1.29 (m, 4H).

M⁻(APCI⁻): 575.

Example 104 Methyl5-[(4-{2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-5-oxopentanoatea) Preparation of tert-butyl2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate(Compound B of Scheme 2)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (1.0g, 3.98 mmol) in anhydrous pyridine (20 mL) was added dropwise methyl6-chloro-6-oxohexanoate (Aldrich) (660 μL, 4.78 mmol) at rt. After 90min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 960mg) was added and the resulting mixture was stirred for 20 hrs at rt.After filtration and rinsing the resin, water (200 mL) was added intothe filtrate and a white solid precipitated out. Filtration and washingwith water gave a white solid, which was dried under vacuo at 70° C. for3 hrs. The title compound (1.27 g) was obtained as a white solid (80%)in 95.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 125-127° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 10.15 (s, 1H), 10.05 (s, 1H), 8.84 (s, 1H),7.80 (d, J=8.5 Hz, 7.65 (d, J=8.5 Hz, 2H), 3.58 (s, 3H), 2.40 (m, 4H),1.8 (m, 2H), 1.78 (s, 9H).

M⁻(APCI⁻): 378.

b) Preparation of methyl5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl)phenyl)amino]-5-oxopentanoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3one in acetic acid in the presence of 5% TFA wasadded tert-butyl2-{4-[(6-methoxy-6-oxohexanoyl)amino]benzoyl}hydrazinecarboxylate. Afterstirring at 100° C., the reaction mixture was cooled to rt and a yellowsolid precipitated out. Filtration on a fritté, washing with AcOH, waterand drying under vacuo at 70° C. for 21 hrs gave 546 mg of the titlecompound (93%) as a yellow solid in 99.2% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

M.p. 282° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 11.45 (s, 1H), 10.31 (s, 1H),7.86-7.78 (m, 5H), 7.70 (d, J=8.29 Hz, 1H), 6.80 (d, J=8.29 Hz, 1H),3.59 (s, 3H), 2.35 (m, 4H), 1.80 (m, 2H).

M⁻(APCI⁻): 533.

Example 1058-[(4-{(2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-8-oxooctanoicacid

Into a suspension of methyl8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-8-oxooctanoate(420 mg, 0.73 mmol) in THF/H₂O (2/1) (15 mL) was added NaOH (1.0 N, 3.6mL). The resulting solution was stirred at rt for 2.5 hr and quenchedwith HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration,washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrsgave the title compound as a yellow powder (340 mg, 82%) in 99.1% purityby HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 276° C. (decomp).

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s,1H), 11.97 (s, 1H), 11.46 (s, 1H),10.27 (s, 1H), 7.82 (m, 5H), 7.70 (d, J=7.9 Hz, 1H), 6.80 (d, J=7.9 Hz,1H), 2.36 (m, 2H), 2.20 (m, 2H), 2.20 (m, 4H), 1.29 (m, 4H).

M⁻(APCI⁻): 561.

Example 1068-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-8-oxooctanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

A solution of N-methyl-D-glucamine (127 mg, 0.66 mmol) and8-[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-8-oxooctanoicacid (331 mg, 0.55 mmol) in MeOH/DMSO (5/1) (120 mL) was stirred at 70°C. for 15 min. The heating bath was removed and Et₂O (500 mL) was added.A yellow solid precipitated out. Filtration, washing with Et₂O (5×10 mL)and drying under vacuo at 40° C. for 96 hrs gave a title compound as ayellow solid (331 mg, 79%) in 98.9% purity by HPLC (MaxPlot detectionbetween 230 and 400 nm).

M.p. 238° C. (decomp).

Example 1076-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-6-oxohexanoicacid

Into a suspension of methyl6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-6-oxohexanoate(405 mg, 0.74 mmol) in THF/H₂O (2/1) (15 mL) was added NaOH (1.0 N, 3.7mL). The resulting solution was stirred at rt for 2.5 hr and quenchedwith HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration,washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrsgave the title compound as a yellow powder (363 mg, 91%) in 99.0% purityby HPLC (MaxPlot detection between 230 and 400 mn).

M.p. 286° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 12.03 (s, 1H), 11.45 (s, 1H),10.29 (s, 1H), 7.70 (m, 6H), 6.82 (m, 1H), 2.36 (m, 2H), 2.24 (m, 2H),1.75 (m, 2H), 1.58 (m, 2H).

M⁻(APCI⁻): 533.

Example 1086-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-6-oxohexanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

A solution of N-methyl-D-glucamine (125 mg, 0.64 mmol) and6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-6-oxohexanoicacid (297 mg, 0.56 mmol) in MeOH/DMSO (5/1) (60 mL) was stirred at 70°C. for 15 min. The heating bath was removed and Et₂O (250 mL) was added.A yellow solid precipitated out Filtration, washing with Et₂O (6×10 mL)and drying under vacuo at 60° C. for 15 hrs gave a title compound as ayellow solid (311 mg, 76%) in 99.3% purity by HPLC (MaxPlot detectionbetween 230 and 400 nm).

M.p. 223° C. (decomp).

Example 1094-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-4-oxobutanoicacid

Into a suspension of methyl4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]4-oxobutanoate(250 mg, 0.48 mmol) in THF/H₂O (2/1) (10 mL) was added NaOH (1.0 N, 2.4mL). The resulting solution was stirred at rt for 1.5 hr and quenchedwith HCl (5 N, 2 mL). A yellow solid precipitated out. Filtration,washing with water (2×5 mL) and drying under vacuo at 70° C. for 20 hrsgave the title compound as a yellow powder (83 mg, 34%) in 99.2% purityby HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 299° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.82 (s, 1H), 12.16 (s, 1H), 11.46 (s, 1H),10.38 (s, 1H), 7.82 (m, 5H), 7.70 (d, J=7.9 Hz, 1H), 6.81 (d, J=7.9 Hz,1H), 2.60 (d, J=5.3 Hz, 2H), 2.54 (d, J=5.7 Hz, 2H).

M⁻(APCI⁻): 505.

Example 1104-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-4-oxobutanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (30 mg, 0.15 mmol) in MeOH (10mL) at reflux was added a solution of4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]oxobutanoicacid (70 mg, 0.14 mmol) in warm DMSO (2 mL). After 10 min of stirring,the heating bath was removed and Et₂O (50 mL) was added. A yellow solidprecipitated out Filtration, washing with Et₂O (6×3 mL) and drying undervacuo at 60° C. for 15 hrs gave a title compound as a yellow solid (75mg, 77%) in 99.5% purity by HPLC (MaxPlot detection between 230 and 400nm).

M.p. 203° C.

Example 1115-[(4-{[(2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-5-oxopentanoicacid

Into a suspension of methyl5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-5-oxopentanoate(502 mg, 0.94 mmol) in THF/H₂O (2/1) (20 mL) was added NaOH (1.0 N, 4.7mL). The resulting solution was stirred at rt for 2 hr and quenched withHCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washingwith water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave thetitle compound as a yellow powder (381 mg, 77%) in 98.3% purity by HPLC(MaxPlot detection between 230 and 400 mn).

M.p. 296° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.81 (s, 1H), 12.09 (s, 1H), 11.46 (s, 1H),10.31 (s, 1H), 7.86-7.78 (m, 5H), 7.70 (d, J=8.29 Hz, 1H), 6.80 (d,J=8.29 Hz, 1H), 2.43 (m, 2H), 2.30 (m, 2H), 1.8 (m, 2H).

M⁻(APCI⁻): 519.

Example 1125-[(4-{[(2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]-5-oxopentanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (128 mg, 0.66 mmol) in MeOH (50mL) at reflux was added a solution of5-[(4-{[(2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]-5-oxopentanoicacid (310 mg, 0.60 mmol) in DMSO (10 mL). After 10 min of stirring, theheating bath was removed and Et₂O (250 mL) was added. A yellow solidprecipitated out. Filtration, washing with Et₂O (6×5 mL) and dryingunder vacuo at 60° C. for 15 hrs gave a title compound as a yellow solid(350 mg, 83%) in 99.9% purity by HPLC (MaxPlot detection between 230 and400 nm).

M.p. 228° C. (decomp.).

Example 1134-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]carbonyl}benzoicacid

Into a suspension of methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]carbonyl)benzoate(546 mg, 0.96 mmol) in THF/H₂O (2/1) (20 mL) was added NaOH (1.0 N, 4.8mL). The resulting solution was stirred at rt for 2 hr and quenched withHCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washingwith water (4×5 mL) and drying under vacuo at 70° C. for 20 hrs gave thetitle compound as a yellow powder (451 mg, 86%) in 97.0% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 362° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.85 (br s, 1H), 13.28 (br s, 1H), 11.47(s, 1H), 10.78 (s, 1H), 8.07 (s, 4H), 8.03 (d, J=8.3 Hz, 2H), 7.92 (d,J=8.3 Hz, 2H), 7.83 (s, 1H), 7.71 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1 Hz,1H).

M⁻(APCI⁻): 553.

Example 1144-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]carbonyl}benzoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (204 mg, 1.05 mmol) in MeOH (80mL) at reflux was added a solution of4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]carbonyl}benzoicacid (387 mg, 0.70 mmol) in warm DMSO (20 mL). After 10 min of stirring,the heating bath was removed and Et₂O (300 mL) was added. A yellow solidprecipitated out. Filtration, washing with Et₂O (5×5 mL) and dryingunder vacuo at 40° C. for 15 hrs gave a title compound as a yellow solid(432 mg, 81%) in 97.9% purity by HPLC (MaxPlot detection between 230 and400 nm).

M.p. 133° C. (decomp.).

Example 115 Methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)amino]carbonyl}benzoatea) Preparation of 4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoicacid (Compound C)

Into a solution of 4-(aminomethyl)amino benzoic acid (5.0 g, 33.1 mmol)in anhydrous THF (200 mL) were added DIEA (12.45 mL, 72.7 mmol) andtert-butyl dimethyl chlorosilane (5.48 g, 36.4 mmol). The resultingmixture was allowed to stir at rt for 1 hr and methyl4-(chlorocarbonyl)benzoate (7.23 g, 36.4 mmol) was added neat. Afterovernight stirring at rt, the reaction mixture was quenched with HCl(0.1N, 250 mL) until pH=1. Extraction with EtOAc/THF (400 mL), dryingover MgSO₄, evaporation under vacuo gave the title compound as a whitepowder (7.0 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 12.87 (s, 1H), 9.33 (t, J=5.8 Hz, 1H), 8.05(m, 4H), 7.91 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 4.56 (d, J=5.8Hz, 2H), 3.88 (s, 3H).

M⁺(ESI (LC/MS)⁺): 314. M⁻(ESI (LC/MS)⁻): 312.

b) Preparation of tert-butyl2-[4-({[4-(methoxycarbonyl)benzoyl]amino}-methyl)-benzoyl]hydrazinecarboxylate(Compound B, Scheme 2)

Into a solution of 4-({[4-(methoxycarbonyl)benzoyl]amino}methyl)benzoicacid (1.0 g, 3.19 mmol) and N-methyl morpholine (420 μL, 3.83 mmol) inanhydrous THF (25 mL) at 0° C. was added isobutyl chloroformate (455 μL,3.51 mmol) then tert-butyl hydrazine carboxylate (1.12 mg, 7.66 mmol).After stirring at 0° C. for 1 hr and overnight at rt, the reactionmixture was quenched with HCl (1N, 25 mL). Extraction with EtOAc (2×25mL), drying over MgSO₄ and evaporation under vacuo gave a residue.Purification by flash chromatography (SiO₂, EtOAc) gave the titlecompound (773 mg, 55%) as a white powder.

¹H NMR (300 MHz, DMSO-d₆) δ 10.16 (s, 1H), 9.31 (t, J=5.9 Hz, 1H), 8.89(s, 1H), 8.05 (m, 4H), 7.82 (d, J=7.7 Hz, 2H), 7.42 (d, J=7.7 Hz, 2H),4.55 (d, J=5.9 Hz, 2H), 3.88 (s, 3H), 1.42 (s, 9H).

M⁻(ESI (LC/MS)⁻): 426.

c) Preparation of methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)amino]carbonyl}benzoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-[4-({[4-(methoxycarbonyl)benzoyl]amino)methyl)benzoyl]hydrazinecarboxylate.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 70° C. for 15 hrs gave 614 mg ofthe title compound (86%) as a yellow solid in 97.9% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 323° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.83 (s, 1H), 11.46 (s, 1H), 9.34 (t, J=7.5Hz, 1H), 8.04 (m, 4H), 7.84 (m, 3H), 7.71 (d, J=8.3 Hz, 1H), 7.55 (d,J=7.9 Hz, 2H), 6.80 (d, J=8.3 Hz, 1H), 4.58 (d, J=7.5 Hz, 2H), 3.87 (s,3H).

M⁻(APCI⁻): 581. M⁺(APCI⁺): 583.

Example 1164-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzyl)amino]carbonyl}benzoicacid

Into a suspension of methyl4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)amino]caxbonyl}benzoate(510 mg, 0.88 mmol) in THF/H₂O (2/1) (20 mL) was added NaOH (1.0 N, 4.4mL). The resulting solution was stirred at rt for 1.5 hr and quenchedwith HCl (5 N, 4 mL). An orange solid precipitated out. Filtration,washing with water (4×5 mL) and drying under vacuo at 70° C. for 20 hrsgave the title compound as a yellow powder (436 mg, 84%) in 96.3% purityby HPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 13.83 (s, 1H), 13.21 (s, 1H),11.46 (s, 1H),9.33 (br s, 1H), 8.02 (m, 4H), 7.85 (m, 3H), 7.70 (d, J=8.3 Hz, 1H),7.55 (d, J=7.2 Hz, 2H), 6.79 (d, J=8.3 Hz, 1H), 4.60 (br s, 2H).

M⁻(APCI⁻): 567.

Example 1174-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro3H-indol-3-3-ylidene)hydrazino]-carbonyl}benzyl)amino]carbonyl}benzoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (157 mg, 0.80 mmol) in MeOH (50mL) at reflux was added a solution of4-{[(4-{[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)amino]carbonyl}benzoicacid (380 mg, 0.67 mmol) in THF (10 mL). After 10 min of stirring, theheating bath was removed and Et₂O (50 mL) was added. A yellow solidprecipitated out. Filtration, washing with Et₂O (3×50 mL) and dryingunder vacuo at 60° C. for 24 hrs gave a title compound as a yellow solid(400 mg, 78%) in 98.9% purity by HPLC (MaxPlot detection between 230 and400 nm).

M.p. 301° C.

Example 118 Benzyl(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenoxy)-3-phenylpropanoatea) Preparation of tert-butyl 2-(4-hydroxybenzoyl)hydrazinecarboxylate(Precursor of Compound B)

Into a solution of 4-hydroxybenzo hydrazide (5.0 g, 32.86 mmol) inanhydrous THF (200 mL) was added a solution of di-tert-butyl dicarbonate(Aldrich) (7.53 g, 34.51 mmol) in anhydrous THF (10 mL). The resultingmixture was stirred at rt for 6 d. After addition of Et₂O (800 ml), awhite solid precipitated out. Filtration, washing with Et₂O (3×20 mL)and drying under vacuo at 50° C. for 5 hr gave the title compound (5.32g, 64%) as a white powder in a in 99.9% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.91 (s, 1H), 8.77 (s, 1H),7.72 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 1.41 (s, 9H).

b) Preparation of tert-butyl2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate(Compound B)

Into a solution of tert-butyl 2(4-hydroxybenzoyl)hydrazinecarboxylate(200 mg, 0.79 mmol) and benzyl (R)-(+)-2-hydroxy-3-phenylpropionate(Aldrich) (270 μL, 1.19 mmol) were added triphenylphosphine polymerbound (Fluka, 3 mmol/g, 400 mg) and diethyl azodicarboxylate (190 μL) at0° C. The resulting mixture was allowed to stir for 2 hr at 0° C. Afterfiltration and rinsing the resin with DCM, the filtrate was evaporatedoff under vacuo to give a brown residue. Purification by flashchromatography (SiO2, AcOEt/chexanes (2/3)) gave the title compound as awhite powder (216 mg, 56%) in 99.4% purity by HPLC (MaxPlot detectionbetween 230 and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.04 (s, 1H), 8.83 (s, 1H), 7.76 (d, J=8.5Hz, 2H), 7.33-7.20 (m, 10H), 6.94 (d, J=8.7 Hz, 2H), 5.32 (t, J=6.4 Hz,1H), 5.13 (d, J=12.4 Hz, 1H), 5.08 (d, J=12.4 Hz, 1H), 3.22 (d, J=6.4Hz, 2H), 1.41 (s, 9H).

M⁻(APCI⁻): 489.

c) Preparation of benzyl(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenoxy)-3-phenylpropanoate

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-{4-[(1S)-1-benzyl-2-(benzyloxy)-2-oxoethoxy]benzoyl}hydrazinecarboxylate.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. for 15 hrs gave 164 mg ofthe title compound (76%) as a yellow solid in 98.8% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 194° C.

¹H NMR (300 MHz, DMSO-d₆) δ 13.76 (s, 1H), 11.46 (s, 1H), 7.80 (m, 3H),7.71 (d, J=8.1 Hz, 1H), 7.28 (m, 10H), 7.08 (d, J=8.3 Hz, 2H), 6.80 (d,J=8.1 Hz, 1H), 5.39 (br s, 1H), 5.13 (s, 2H), 3.26 (br s, 2H).

M⁻(APCI⁻): 644. M⁺(APCI⁺): 646.

Example 119(2S)-2-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbon}phenoxy)-3-phenylpropanoicacid

Into a suspension of benzyl(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenoxy)-3-phenylpropanoate(132 mg, 0.20 mmol) in THF/H₂O (2/1) (5 mL) was added NaOH (1.0 N, 0.5mL). The resulting solution was stirred at rt for 1 hr and quenched withHCl (5 N, 0.5 mL). After addition of water (15 mL), a yellow solidprecipitated out. Filtration, washing with water (3×2 mL) and dryingunder vacuo at 60° C. for 15 hrs gave the title compound as a yellowpowder (83 mg, 73%) in 99.4% purity by HPLC (MaxPlot detection between230 and 400 nm).

M.p. 285° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.76 (s, 1H), 13.31 (s, 1H), 11.45 (s, 1H),7.81 (m, 3H), 7.70 (d, J=7.8 Hz, 1H), 7.32-7.21 (m, 5H), 7.06 (d, J=8.3Hz, 2H), 6.80 (d, J=7.8 Hz, 1H), 5.17 (m, 1H), 3.21 (m, 2H).

M⁻(APCI⁻): 554.

Example 120(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenoxy)-3-phenylpropanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (160 mg, 0.82 mmol) in MeOH (50mL) at reflux was added(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenoxy)-3-phenylpropanoicacid (396 mg, 0.71 mmol). After 10 min of stirring, the heating bath wasremoved and Et₂O (400 mL) was added. A yellow solid precipitated out.Filtration, washing with Et₂O (4×5 mL) and drying under vacuo at 40° C.for 72 hrs gave a title compound as a yellow solid (346 mg, 64%) in99.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).

M.p. 130° C. (decomp).

Example 121 Methyl4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}-benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoatea) Preparation of methyl4-(5-iodo-2,3-dioxo-2,3-dihydro-1H-indol-1-yl)butanoate (Precursor ofCompound A)

Into a solution of 5-iodo-1H-indole-2,3-dione (1.0 g, 3.66 mmol) inanhydrous THF (18 ml) were added DBU (0.82 mL, 5.49 mmol) and methyl4-bromobutanoate (0.6 mL, 5.49 mmol). After stirring at rt for 2 hrs,the reaction mixture was quenched with water (60 mL) and HCl (IN, 10mL). Extraction with EtOAc (3×50 mL), drying over MgSO₄ and evaporationunder vacuo gave a residue. Purification by flash chromatography(chexanes/Et₂O (1/3)) gave the title compound as an orange powder (1.10g, 71%) in 90.1% purity by HPLC (MaxPlot detection between 230 and 400nm).

¹H NMR (300 MHz, DMSO-d₆) δ 7.97 (dd, J=8.3, 1.9 Hz, 1H), 7.79 (d, J=1.9Hz, 1H), 7.05 (d, J=8.3 Hz, 1H), 3.66 (t, J=6.8 Hz, 2H), 3.55 (s, 3H),2.42 (t, J=7.4 Hz, 2H), 1.81 (m, 2H); M⁺(ESI (LC/MS)⁺): 374.

b) Preparation of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (Compound C ofScheme 2)

To a solution of 3-(3,4methylenedioxyphenyl)-propionic acid (501 mg,2.58 mmol) in anhydrous THF (10 mL) were added N-methylmorpholine (0.28mL, 2.58 mmol) and isobutylchloroformate (0.33 mL, 2.58 mmol) at 0° C.After 30 min, at 0° C., a solution of methyl 4-aminobenzoate (390 mg,2.58 mmol) in anhydrous THF (2 mL) was added to the reaction mixture.After 30 min the temperature was allowed to warm up to rt and stir for24 hrs. After extraction with EtOAc (100 mL), washing with HCl (0.1 N,50 mL) and a saturated aqueous solution of NaHCO₃ (50 mL), the organiclayer was dryed over sodium sulfate and evaporated under vacuo to give asolid. The residue was taken up in Et₂O, filtrated and washed with Et₂Ogave the title compound as a white solid (62%) in a 99.4% purity by HPLC(MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.22 (s, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.70(d, J=8.7 Hz, 2H), 6.82 (d, J=1.6 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.68(dd, J=7.9, 1.6 Hz, 1H), 5.94 (s, 2H), 3.80 (s, 3H), 2.82 (t, J=7.5 Hz,2H), 2.61 (t, J=7.5 Hz, 2H).

c) Preparation of3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide(Scheme 2, compound B)

To a suspension of methyl4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoate (200 mg, 0.61 mmol)in EtOH (3.5 mL) was added hydrazine hydrate (0.5 mL). After stirringfor 15 hrs at reflux, the reaction mixture was cooled to rt and a whitesolid precipitated out. Filtration, washing with EtOH (2×1 mL) and water(3×1 mL), and drying under vacuo at 70° C. for 1 hr gave 130 mg of thetitle compound (65%) as a white solid in 95.5% purity by HPLC (MaxPlotdetection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 10.08 (s, 1H), 9.60 (s, 1H), 7.75 (d, J=8.5Hz, 2H), 7.61 (d, J=8.5 Hz, 2H), 6.82 (d, J=1.5 Hz, 1H), 6.80 (d, J=7.9Hz, 1H), 6.68 (dd, J=7.9, 1.5 Hz, 1H), 5.94 (s, 2H), 4.41 (s, 2H), 2.82(t, J=7.6 Hz, 2H), 2.59 (t, J=7.6 Hz, 2H).

d) Preparation of methyl4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoate

Following the general method as outlined in Example 1, into a suspensionof methyl 4-(5-iodo-2,3oxo-2,3 dihydro-1H-indol-1-yl)butanoate in aceticacid was added3-(1,3-benzodioxol-5-yl)-N-[4-(hydrazinocarbonyl)phenyl]propanamide.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. overnight gave 188 mg ofthe title compound (49%) as a yellow solid in 94.3% purity by HPLC(MaxPlot detection between 230 and 400 mn).

M.p. 230° C. (decomp).

M⁻(APCI⁻): 681.

¹H NMR (DMSO-d₄, 300 MHz) δ 13.75 (s, 1H), 10.32 (s, 1H), 7.84 (m, 6H),7.12 (d, J=8.3 Hz, 1H), 6.82 (m, 2H), 6.70 (d, J=7.9 Hz, 1H), 5.95 (s,2H), 3.79 (m, 2H), 3.55 (s, 3H), 2.84 (t, J=7.4 Hz, 2H), 2.64 (t, J=7.4Hz, 2H), 2.43 (t, J=7.0 Hz, 2H), 1.88 (m, 2H).

Example 1224-{(3Z)-3-[(4-{[3-(1,3-Benzodioxol-5-yl)propanoyl]amino}benzoyl)-hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoicacid

Into a suspension of methyl4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoate(150 mg, 0.22 mmol) in THF/H₂O (2/1) (10 mL) was added NaOH (1.0 N, 1.1mL). The resulting solution was stirred at rt for 2 hr and quenched withHCl (5 N, 4 mL). A yellow solid precipitated out. Filtration, washingwith water (4×10 mL) and drying under vacuo at 60° C. for 15 hrs gavethe title compound as a yellow powder (90 mg, 58%) in 95.5% purity byHPLC (MaxPlot detection between 230 and 400 nm).

¹H NMR (DMSO-d₆, 300 MHz) δ 13.77 (s, 1H), 12.11 (s, 1H), 10.32 (s, 1H),7.84 (m, 6H), 7.12 (d, J=8.3 Hz, 1H), 6.82 (m, 2H), 6.71 (d, J=7.9 Hz,1H), 5.96 (s, 2H), 3.79 (t, J=6.2 Hz, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.64(t, J=7.4 Hz, 2H), 2.33 (t, J=7.0 Hz, 2H), 1.80 (m, 2H).

M⁻(ESI (LC/MS)⁻): 667. M⁺(ESI (LC/MS)⁺): 669.

Example 1234-{3-[(4-{[3-(1,3-Benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt

Into a solution of N-methyl-D-glucamine (161 mg, 0.83 mmol) in MeOH (120mL) at reflux was added a solution of4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoicacid (460 mg, 0.69 mmol) in DMSO (12 mL). After 10 min of stirring, theheating bath was removed and Et₂O (1000 mL) was added. A yellow solidprecipitated out. Filtration, washing with Et₂O (3×50 mL) and dryingunder vacuo at 60° C. for 24 hrs gave a title compound as a yellow solid(424 mg, 71%) in 99.9% purity by HPLC (MaxPlot detection between 230 and400 nm).

M.p. 135-140° C.

Example 124 Methyl3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoatea) Preparation of tert-butyl2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate(Compound B)

To a solution of tert-butyl 2-(4-aminobenzoyl)hydrazinecarboxylate (200mg, 0.80 mmol) in anhydrous pyridine (4 mL) was added dropwise methyl3-(4-chlorosulfonylphenyl)propionate (251 mg, 0.96 mmol) at rt. After 60min, aminomethyl resin (Polymers Laboratories PL-AMS, 1.96 mmol/g, 200mg) was added and the resulting mixture was stirred for 1 hr at rt.After filtration and rinsing the resin, water (100 mL) was added intothe filtrate. Extraction with EtOAc (100 mL), washing with HCl (1N, 60mL) and an aqueous saturated solution of NaHCO₃ (50 mL), drying overMgSO₄ and evaporation under vacuo gave a yellow oil. The residue wastaken up in Et₂O and a white solid precipitated out. Filtration andwashing with Et₂O gave the title compound (214 mg) was obtained as awhite solid (56%) in 99.3% purity by HPLC (MaxPlot detection between 230and 400 nm).

¹H NMR (300 MHz, DMSO-d₆) δ 10.67 (s, 1H), 10.02 (s, 1H), 8.83 (s, 1H),7.70 (m, 4H), 7.40 (d, J=8.3 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 3.52 (s,3H), 2.86 (t, J=7.5 Hz, 2H), 2.63 (t, J 7.5 Hz, 2H), 1.39 (s, 911).

M⁻(APCI⁻): 476.

b) Preparation of methyl3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate(Scheme 1)

Following the general method as outlined in Example 1, into a suspensionof 5-iodo-1H-indole-2,3-dione in acetic acid in the presence of 5% TFAwas added tert-butyl2-[4-({[4-(3-methoxy-3-oxopropyl)phenyl]sulfonyl}amino)benzoyl]hydrazinecarboxylate.After stirring at 100° C., the reaction mixture was cooled to rt and ayellow solid precipitated out. Filtration on a fritté, washing withAcOH, water and drying under vacuo at 60° C. for 60 min gave 206 mg ofthe title compound (87%) as a yellow solid in 98.2% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 316° C. (decomp.).

¹H NMR (300 MHz, DMSO-d₆) δ 13.72 (s, 1H), 11.45 (s, 1H), 10.91 (s, 1H),7.78 (m, 5H), 7.70 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.9 Hz, 2H), 7.30 (d,J=8.3 Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 3.52 (s, 3H), 2.88 (t, J=7.3 Hz,2H), 2.63 (t, J=7.3 Hz, 2H).

M⁻(APCI⁻): 631.

Example 1253-(4-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]sulfonyl}phenyl)propanoicacid

Into a suspension of methyl3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate(166 mg, 0.26 mmol) in THF/H₂O (2/1) (6 mL) was added NaOH (1.0 N, 1.3mL). The resulting solution was stirred at rt for 1 hr and quenched withHCl (5 N, 1.3 mL). A yellow solid precipitated out. Filtration, washingwith water (4×2 mL) and drying under vacuo at 60° C. for 18 hrs gave thetitle compound as a yellow powder (133 mg, 81%) in 99.3% purity by HPLC(MaxPlot detection between 230 and 400 nm).

M.p. 319° C. (decomp).

¹H NMR (300 MHz, DMSO-d₆) δ 13.71 (s, 1H), 12.16 (s, 1H), 11.44 (s, 1H),10.90 (s, 1H), 7.77 (m, 5H), 7.70 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.9 Hz,2H), 7.29 (d, J=8.3 Hz, 2H), 6.79 (d, J=8.1 Hz, 1H), 2.84 (t, J=7.4 Hz,2H), 2.53 (t, J=7.4 Hz, 2H).

M⁻(APCI⁻): 617.

Example 1263-(4-{[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]sulfonyl}phenyl)propanoicacid, N-methyl-D-glucamine(1-deoxy-1-(methylamino)glucitol)salt

Into a solution of N-methyl-D-glucamine (38 mg, 0.19 mmol) in MeOH (15mL) at reflux was added a solution of3-(4-{[(4-{[2-(5-Iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)amino]sulfonyl}phenyl)propanoicacid (109 mg, 0.18 mmol) in warm DMSO (1.5 mL). After 10 min ofstirring, the heating bath was removed and Et₂O (75 mL) was added. Ayellow solid precipitated out. Filtration, washing with Et₂O/MeOH (5/1)(4×2 mL) and Et₂O (4×2 mL ) and drying under vacuo at 60° C. for 15 hrsgave a title compound as a yellow solid (115 mg, 80%) in 99.5% purity byHPLC (MaxPlot detection between 230 and 400 nm).

M.p. 160° C. (decomp).

Example 127 Preparation of a Pharmaceutical Formulation

Pharmaceutical formulations using the compounds of formula (I) may beprepared according to standard procedures known to a person skilled inthe art.

The following formulation examples illustrate representativepharmaceutical compositions using compounds of formula (I), while it isemphasised that the present invention is not to be construed as beinglimited to said the below formulations.

Formulation 1—Tablets

An oxindole hydrazine derivative of formula (I) is admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ratio. Aminor amount of magnesium stearate is added as a lubricant. The mixtureis formed into 240-270 mg tablets (80-90 mg of active oxindole hydrazidecompound per tablet) in a tablet press.

Formulation 2—Capsules

An oxindole hydrazide derivative of formula (I) is admixed as a drypowder with a starch diluent in an approximate 1:1 weight ratio. Themixture is filled into 250 mg capsules (125 mg of active oxindolehydrazide compound per capsule).

Formulation 3—Liquid

An oxindole hydrazide derivative of formula (I) (1250 mg), sucrose (1.75g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S.sieve, and then mixed with a previously prepared solution ofmicrocrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are dilutedwith water and added with stirring. Sufficient water is then added.

Formulation 4—Tablets

An oxindole hydrazide derivative of formula (I), is admixed as a drypowder with a dry gelatin binder in an approximate 1:2 weight ratio. Aminor amount of magnesium stearate is added as a lubricant. The mixtureis formed into 450-900 mg tablets (150-300 mg of active oxindolehydrazide compound) in a tablet press.

Formulation 5—Injection

An oxindole hydrazide derivative of formula (I), is dissolved in abuffered sterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/ml.

Example 128 Biological Assays

The compounds of formula (I), may be subjected to the following assays:

-   -   (1) The PTP Enzyme Assay    -   (2) The in vivo assay in db/db mice        (1) The PTP Enzyme Assay (In Vitro Assay)

The PTP Enzyme Assay aims at determining the extent of inhibition of theexamined PTP (e.g. PTP1B, TC-PTP, PTP-β, DEP-1, LAR, SHP-1, SHP-2,GLEPP-1, PTP-κ, PTP-μ, VHR, hVH5) in the presence of a test compound.The inhibition is illustrated by IC₅₀ values which denote theconcentration necessary to achieve an inhibition of 50% of the givenPTP.

a) PTPs Cloning

The cloning and expression of the catalytic domain of PTPs (e.g. PTP1B,TC-PTP, PTP-β, DEP-1, LAR, SHP-1, SHP-2, GLEPP-1, PTP-κ, PTP-μ, VHR,hVH5) maybe performed as described in J. Biol. Chem. 2000, 275(13), pp9792-9796.

b) Materials and Methods

Assays were performed in a 96 well plate format, using the catalyticcore of a human recombinant PTP, as an enzyme and6,8-DiFluoro-4-MethylUmbelliferyl Phosphate (DiFMUP, Molecular Probes,D-6567) as a substrate at the Km value which was predetermined for eachenzyme. Compounds to be tested were dissolved in 100% DMSO at aconcentration of 2 mM. Subsequent dilutions of the test compounds (toyield a concentration of 100, 30, 10,.3, 1,0.3, 0.1,0.03, 0.01, 0.001μM) were performed in 100% DMSO using a Tecan Stand Alone Workstation. 5μl of diluted compound or vehicle (100% DMSO) was distributed to a blackCostar 96 well plate. 25 μl of DiFMUP diluted in the assay buffer (20 mMTris HCl pH 7.5, 0.01% IGEPAL CA-630, 0.1 mM ethylenediaminetetraceticacid, 1 mM DL-Dithiothreitol) were added, followed by 20 μl of humanrecombinant PTP enzyme diluted in assay buffer in order to start thereaction. The reaction ran for 30 minutes at room temperature beforereading the fluorescence intensity on a Perkin-Elmer Victor 2spectrofluorimeter (excitation at 355 nm, emission at 460 nm, for 0.1s). The percentage of inhibition relative to the fluorescence observedin the presence of solvent (5% DMSO) alone was determined. The IC50values for inhibition were determined in triplicates on at least 3separate occasions.

The tested compounds according to formula (I), displayed an inhibition(illustrated by IC₅₀ values) with regard to PTP1B, TC-PTP, SHP andGLEPP-1 of less than 30 μM, in an embodiment an inhibition (illustratedby IC₅₀ values) of less than 10 μM.

The compound of Example no. 1 for instance displays an inhibition (IC₅₀)with regard to PTP1B of 340 nM, and of about 496 nM with regard toGLEPP-1. The compound mentioned in Example no. 70 displays an inhibition(IC₅₀) with regard to PTP1B of 770 nM.

(2) In Vivo Assay in db/db Mice

The following assay aims at determining the anti-diabetic effect of thetest compounds of formula (I), in vivo in db/db mice using either fasted(to determine the postprandial glycemia right after a predetermineddiet), or fed animals, to determine glycemia after a predeterminedperiod of treatment.

The assays were performed as follows:

2 groups of db/db mice, 6 animals each, were formed, in the first onemice were fasted during 20 hours, the second one comprises fed (adlibitum) mice.

Group 1: The fasted animals (6) were administered (per os) a dose of 100mg/kg of the test compound according to formula (I).

After oral administration with compounds of formula (I), they had accessto commercial food (ad libitum). Blood glucose (postprandial glycemia)was determined before and 4 hrs after drug administration. Treatmentdecreased the blood glucose level induced by food intake by about20-40%.

For example the compounds of Example 1(N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl)phenyl)-3-phenylpropanamide)and of Example 50(N-4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)benzamide)caused a reduction of blood glucose level of 30%, while the compound ofExample no 18(N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4-nitrophenoxy)aceto-hydrazide)yielded a corresponding reduction of 34%.

Group 2: The fed animals (6) were administered (per os) a dose of 5×50mg/kg of the test compound according to formula (I).

Mice were orally treated once daily during 5 days with compounds offormula (I). Blood glucose was determined before drug administration and16 hrs after the last drug administration. A repeated oraladministration (per os) using said compounds decreased the blood glucoselevel by about 10-30%.

The compounds of Example 1(N-(4-([2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide),23 (Methyl 4-{2-[2-(5-iodo-2-oxo-1,2dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate) and 26(N-(5-Iodo-2-oxo-1,2hydro-3H-indol-3-ylidene)-3-phenoxybenzohydrazide),for instance, caused a reduction of the blood glucose level of 22%, 30%and 17% respectively.

1. An oxindole hydrazide of formula (II)

wherein A is O or a bond; B is independently optionally substitutedphenyl, naphthyl, phenantrenyl, pyrrolyl, furyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, [1,3]thiazolo[3,2-b][1,2,4]triazolyl, carbazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,1,2,3-oxadiazolyl, benzo (2, 1, 3) oxadiazolyl, benzo (1,2,5)oxadiazolyl, 1,2,4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3,4-oxadiazolyl,tetrazolyl, 1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3-dihydro]benzofuryl, isobenzofuryi, benzothienyl, benzotriazolyl,isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, pyridazinyl, pyrirnidyl, quinolizinyl,quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl,quinolyl, isoquinolyl, tetrazolyl, 5,6,7,8-tetrahydroquinolyl,5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl,xanthenyl, benzoquinolyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, oxolanyl, pyrolidinyl,pyrazolidinyl, piperidinyl, piperazinyl, pyridyl, imidazolidinyl,1,2,4-oxadiazolidinyl, 1,2,5-oxadiazolidinyl, 1,3,4-oxadiazolidinyl,isoxazolidinyl or morpholinyl; R⁸ is selected in the group consisting ofH, halogen, cyano, (C₁-C₆)alkyl, aryl, heteroaryl, —SO—R⁹,—SO₂—R⁹,(C₁-C₆)alkyl-SO₂—R⁹, —NO₂, —N(R⁹)₂, (C₁-C₆)-alkyl-O—R⁹, —SR⁹,—SO₂—R⁹, —(C═O)O—R⁹, —(C═O)—R⁹, —(C═O)N(R⁹)₂, —(C═O)NH—R⁹,—(C═O)NR⁹—N(R⁹)₂, —NR⁹—(C═O)—N(R⁹)₂, —NR⁹—(SO₂—R⁹), —NH—(C═O)—R⁹,(C₁-C₆)-alkyl-NH—(C═O)—R⁹, —NR⁹—(C═O)—R⁹ wherein R⁹ is selected from thegroup consisting of H, C₃-C₈ cycloalkyl, 3-8 membered heterocycloalkylwhich may contain 1-2 further heteroatoms selected from O, N or S,(C₁-C₆)-alkyl-heterocycloalkyl wherein said heterocycloalkyl may contain1-2further heteroatoms selected from O, N or S, aryl,(C₁-C₆)-alkyl-aryl, (C₁-C₆)-alkoxy-aryl, heteroaryl,(C₁-C₆)-alkyl-heteroaryl or (C₁-C₆)-alkoxy-heteroaryl, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-COOR¹⁰ wherein R¹⁰ is H or (C₁-C₆)alkyl or —NH₂ m′ is 0 or1; p is an integer from 1 to 3; with the proviso that the followingcompounds are excluded:


2. An oxindole hydrazide according to claim 1, wherein B is a phenylgroup and m′ is
 0. 3. An oxindole hydrazide according to claim 2 whereinm′ is 0, p is 0 or 1, A is a bond or O, B is a phenyl group and R⁸ isselected in the group consisting of —O₂, —CO₂—R⁹ and —NH—(C═O)—R⁹wherein R⁹ is selected from the group consisting of H, C₃-C₈ cycloalkyl,3-8 membered heterocycloalkyl which may contain 1-2 further heteroatomsselected from O , N or S, (C₁-C₆)-alkyl-heterocycloalkyl wherein saidheterocycloalkyl may contain 1-2 further heteroatoms selected from O, Nor S, aryl, (C₁-C₆)-alkyl-aryl, (C₁-C₆)-alkoxy-aryl, heteroaryl,(C₁-C₆)-alkyl-heteroaryl or (C₁-C₆)-alkoxy-heteroaryl, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-COOR¹⁰ wherein R¹⁰ is H or (C₁-C₆)alkyl or —NH₂.
 4. Anoxindole hydrazide according to claim 1, wherein said oxindole hydrazideis selected from the group consisting of:N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide;3,5-Dichloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methylbenzohydrazide;4-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;3-Hydroxy-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-nitrobenzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-phenoxybenzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(trifluoromethyl)benzohydrazide;4-tert-Butyl-N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)[1,1′-biphenyl]-4-carbohydrazide;4-Bromo-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-nitrobenzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-methoxybenzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-methoxybenzohydrazide;4-Amino-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;4-(Dimethylamino)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-lidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4-nitrophenoxy)acetohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(trifluoromethoxy)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,1,3-benzoxadiazole-5-carbohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-((5-nitro)-2-furohydrazide);Methyl4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoate;Methyl4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate;4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoicacid;4-Iodo-N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-phenoxybenzohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(4-iodophenoxy)acetohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[(4-methylphenyl)sulfonyl]acetohydrazide;2-{[(2-Furylmethyl)sulfonyl]methyl}-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4-carbohydrazide;2-Hydroxy-N′-(-5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N-(2-Furylmethyl)-N′-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}urea;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(methylsulfanyl)benzohydrazide; Methyl6-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}nicotinate; Benzyl4-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazine]-2-oxoethoxy}benzoate;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-2-furamide;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)hexanamide;4-Cyano-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide;4-(Hexyloxy)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide;4-Heptyl-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide;2-{2-Nitro-4,5-dimethoxyphenyl}-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-yliden)acetohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1-(3-pyridinylmethyl)-4-piperidinecarbohydrazide;2-Amino-5-nitro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;2-[5-(3-Nitrophenyl)-2H-tetrazo1-2-yl]-N′-(5-iodo-2-oxo1,2-dihydro-3H-indol-3-ylidene)acetohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(1-pyrrolidinyl)-2H-tetrazol-2-yl]acetohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide;4-{2-[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoicacid;4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-phenylbenzamide;4-Cyano-N-(3-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide;N′-[5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]-4-[4-(4-morpholinylmethyl)phenoxy]benzohydrazide;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)benzamide;4-(Benzyloxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N-(3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenyipropanamide;4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-N-{3-[(trifluoromethyl)sulfonyl]phenyl}benzamide;4-Chloro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}benzyl)benzamide; Methyl4-{3-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzoate;2-[(2-Chlorophenoxy)methyl]-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-1,3-thiazole-4-carbohydrazide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-(2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazol-6-yl)acetohydrazide;4-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-N′-[5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene]butanohydrazide;2-{[3-Chloro-5-(trifluoromethyl)-2-pyridinyl]amino}-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide;1-Benzoyl-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-piperidinecarbohydrazide;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3- ylidene)hydrazino]carbonyl}phenyl)-2-phenoxyacetamide;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-nicotinamide;3-Nitro-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-benzyl)benzamide;N-(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)[1,1′-biphenyl]-4-carboxamide;Methyl-3-{2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate;Methyl-4-{[[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino](oxo)acetyl]-amino}benzoate;3-(1,3-Benzodioxol-5-yl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazine]carbonyl}phenyl)propanamide;4-[(4-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzoyl)-amino]benzoic acid;3-(3,4-Dihydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)propanamide;3-(3-Hydroxyphenyl)-N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)propanamide;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-6-methoxy-5-nitronicotinohydrazide;3-{[2-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]sulfonyl}benzoicacid; 2-Hydroxy-5-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]sulfonyl}-benzoic acid;N′-(5-Iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-5-(2-pyridinyl)-2-thiophenesulfono-hydrazide;4-Chloro-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-3-nitrobenzenesulfono-hydrazide;Methyl-{3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate;N-Dodecyl-3-[(4-hydroxybenzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indole-1-carboxamide;Methyl-(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetate;(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid;(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid, tromethanine (2-amino-2-hydroxymethyl-1,3-propanediol)salt;(3-{[4-(hexanoylamino)benzoyl]hydrazono}-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol)salt;2-(4-cyanophenoxy)-N′-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)acetohydrazide;4-({2-[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethyl}thio)-3-nitrobenzenesulfonamide;N-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-N-methyl-3-phenyipropanamide;methyl-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}acetate;methyl-4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-4-oxobutanoate;3-(1,3-benzodioxol-5-yl)-N-(4-{[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-hydrazine]carbonyl}phenyl)propanamide;{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}aceticacid;{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}aceticacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino) glucitol)salt;methyl-6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-6-oxohexanoate;methyl-4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]carbonyl}benzoate;methyl-8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-8-oxooctanoate;methyl-5-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]-5-oxopentanoate;8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-8-oxooctanoic acid;8-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-8-oxooctanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt;6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-6-oxohexanoicacid; 6-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-6-oxohexanoic acid,N-methyl-D-glucamine (1- deoxy-1-(methylamino)glucitol) salt;4-[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-4oxobutanoicacid;4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazine]carbonyl}benzyl)-amino]carbonyl}benzoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)-glucitol) salt;5-[(4-{[(2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-5-oxopentanoicacid; 5-[(4-{[(2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]-5-oxopentanoic acid,N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt;4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]carbonyl}benzoicacid; 4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-amino]carbonyl}benzoic acid,N-methyl-D-giucamine (1-deoxy-1-(methylamino)-glucitol) salt;methyl-4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-benzyl)amino]carbonyl}benzoate;4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}benzyl)-amino]carbonyl}benzoic acid;4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazine]carbonyl}benzyl)-amino]carbonyl}benzoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)-glucitol) salt;benzyl-(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenoxy)-3-phenylpropanoate;(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenoxy)-3-phenyipropanoicacid;(2S)-2-(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenoxy)-3-phenyipropanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino) glucitol) salt;methyl-4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazonoll-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoate;4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-odo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoic acid;4-{3-[(4-{[3-(1,3-benzodioxol-5-yl)propanoyl]amino}benzoyl)hydrazono]-5-iodo-2-oxo-2,3-dihydro-1H-indol-1-yl}butanoicacid, N-methyl-D-glucamine (1-deoxy-1-(methylamino)glucitol) salt;methyl-3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-carbonyl}phenyl)amino]sulfonyl}phenyl)propanoate;3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]sulfonyl}phenyl)propanoic acid; and3-(4-{[(4-{[2-(5-iodo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)amino]sulfonyl}phenyl) propanoic acid, N-methyl-D-glucamine(1-deoxy-1-(methylamino) glucitol) salt.
 5. An oxindole hydrazideselected from the group consisting of:4-Nitro-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;Methyl-4-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate;4-Methoxy-N′-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)benzohydrazide;N-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}phenyl)-3-phenylpropanamide;N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-{3-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-3-oxopropyl}benzohydrazide;N-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-phenyl)-2-phenoxyacetamide;N-(4-{[2-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]carbonyl}-benzyl)-3-nitrobenzamide;Methyl3-{2-[2-(5-bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)hydrazino]-2-oxoethoxy}benzoate;N′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2-[4-(1H-tetrazol-5-yl)phenoxy]acetohydrazide; andN′-(5-Bromo-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-4-(1H-tetrazol-5-yl)benzohydrazide.6. An oxindole hydrazide of formula (II):

wherein A is O or a bond; wherein B is selected from the groupconsisting of phenyl, biphenyl, benzo (1,2,5) oxadiazolyl, furyl,thiadiazolyl, thienyl, thiazolyl, indolyl, piperidinyl, tetrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl and pyridyl; R⁸ is selected in thegroup consisting of H, halogen, cyano, (C₁-C₆)alkyl, aryl, heteroaryl,—SO—R⁹, —SO₂, —R⁹, (C₁-C₆)alkyl-SO₂—R⁹, —NO₂, —N(R⁹)₂,(C₁-C₆)-alkyl-O—R⁹, —SR⁹, —SO₂—R⁹, —(C═O)O—R⁹, —(C═O)—R⁹, —(C═O)N(R⁹)₂,—(C═O)NH—R², —(C═O)NR⁹—N(R⁹)₂, —NR⁹—(C═O)—N(R⁹)₂, —NR⁹—(SO₂—R⁹),—NH—(C═O)—R⁹, (C₁-C₆)-alkyl-NH—(C═O)-R⁹, —NR⁹—(C═O)—R⁹ wherein R⁹ isselected from the group consisting of H, C₃-C₈ cycloalkyl, 3-8 memberedheterocycloalkyl which may contain 1-2 further heteroatoms selected fromO, N or S, (C₁-C₆)-alkyl-heterocycloalkyl wherein said heterocycloalkylmay contain 1-2 further heteroatoms selected from O, N or S, aryl,(C₁-C₆)-alkyl-aryl, (C₁-C₆)-alkoxy-aryl, heteroaryl,(C₁-C₆)-alkyl-heteroaryl or (C₁-C₆)-alkoxy-heteroaryl, (C₁-C₆)-alkyl,(C₁-C₆)-alkyl-COOR¹⁰ wherein R¹⁰ is H or (C₁-C₆)alkyl or —NH₂ m′ is 0 or1; p is an integer from 1 to 3; with the proviso that the followingcompounds are excluded:


7. A pharmaceutical composition comprising at least one oxindolehydrazide according to claim 1, and a pharmaceutically acceptablecarrier, diluent or excipient thereof.
 8. A method of preparing anoxindole of formula (I) according to claim 1, which comprises: reactingA and B as follows:


9. A method according to claim 8, wherein compound B is prepared by aprocess, which comprises: reacting (C) with PG-NH—NH—R³ as follows:

wherein R is C₁-C₆ alkyl group and PG, R, A, B, R⁸ m, n and p are asabove defined.